Hindawi Publishing CorporationISRN HepatologyVolume 2013 Article ID 534972 21 pageshttpdxdoiorg1011552013534972

Review ArticleRoles of Vitamin A Metabolism in the Development ofHepatic Insulin Resistance

Guoxun Chen

Department of Nutrition University of Tennessee at Knoxville Knoxville TN 37996 USA

Correspondence should be addressed to Guoxun Chen gchen6utkedu

Received 2 July 2013 Accepted 18 August 2013

Academic Editors G Batignani S Mandard J J Marin and S Strom

Copyright copy 2013 Guoxun ChenThis is an open access article distributed under the Creative CommonsAttribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The increase in the number of people with obesity- and noninsulin-dependent diabetes mellitus has become a major public healthconcern Insulin resistance is a common feature closely associated with human obesity and diabetes Insulin regulates metabolismat least in part via the control of the expression of the hepatic genes involved in glucose and fatty acid metabolism Insulinresistance is always associated with profound changes of the expression of hepatic genes for glucose and lipid metabolism Asan essential micronutrient vitamin A (VA) is needed in a variety of physiological functions The active metablite of VA retinoicacid (RA) regulates the expression of genes through the activation of transcription factors bound to the RA-responsive elementsin the promoters of RA-targeted genes Recently retinoids have been proposed to play roles in glucose and lipid metabolism andenergy homeostasis This paper summarizes the recent progresses in our understanding of VA metabolism in the liver and of thepotential transcription factors mediating RA responses These transcription factors are the retinoic acid receptor the retinoid Xreceptor the hepatocyte nuclear factor 4120572 the chicken ovalbumin upstream promoter-transcription factor II and the peroxisomeproliferator-activated receptor 120573120575 This paper also summarizes the effects of VA status and RA treatments on the glucose and lipidmetabolism in vivo and the effects of retinoid treatments on the expression of insulin-regulated genes involved in the glucose andfatty acid metabolism in the primary hepatocytes I discuss the roles of RA production in the development of insulin resistancein hepatocytes and proposes a mechanism by which RA production may contribute to hepatic insulin resistance Given the largeamount of information and progresses regarding the physiological functions of VA this paper mainly focuses on the findings inthe liver and hepatocytes and only mentions the relative findings in other tissues and cells

1 Introduction of Vitamin A (VA)

11 The Discovery of VA Dietary energy and nutrients arerequired for the survival of an individual Diets have beenconsidered as nutriments medicines and poisons for thou-sands of years With the development of modern nutritionthe roles of each dietary component in health and diseaseshave been gradually revealed after the understanding of itschemical structures and metabolism This has contributedenormously to the prevention and treatment of diseasesrelated to nutrition abnormalities However the roles ofmicronutrients in the development of chronic metabolicdiseases such as obesity and diabetes have not been clearlydefined

When normal growth of experimental animals was thereadout scientists began to realize that dietary factors other

than proteins carbohydrates pure fats and minerals wereessential as well [1] Lipid- and water-soluble vitamins startedto be recognized and identified after purified diets withdefined components were used to determine essential factorsto support the growth of lab animals [2] VA was the firstlipid-soluble factor being observed and described [3 4]When rats after weaning were fed a synthetic diet with fatstripped of VA for eight weeks their growth stopped Thesomatic growth resumed when VA was added back to thediet [3 4] Since then additional characterizations of VAhavegradually revealed its roles in the general health of a subjectand its use to treat diseases [5]

It has been known now since then VA (retinol) andmolecules with similar physiological activities are essentialmicronutrients for a variety of physiological functions such asvision embryogenesis immunity and differentiation [6]The

2 ISRN Hepatology

development of VA deficiency will cover clinical symptomsranging from night blindness to the increase of mortalityin patients with measles [7] On the other hand excessiveintake of VA from dietary sources or supplements has beenconsidered to be teratogenic [8] In addition when patientswith acne are treated with retinoic acid (RA) drugs such asisotretinoin (13-cisRA) a significant portion of them develophypertriglyceridemia an undesired side effect [9 10] Patientswith acute promyelocytic leukaemia (APL) treated with RAgain body weight [11] Moreover excessive 120573-carotene intakefrom supplements can also cause detrimental effects [12] Allof these observations demonstrate the broad spectrumofVArsquosphysiological functions

12 The Sources and Storage of VA Since humans andmammals do not synthesize VA its nutritional need has to besatisfied through dietary intake Dietary sources of VA existin two forms preformed VA (retinol or retinyl esters) andprovitamin A carotenoids [13] Preformed VA is mainly inthe form of retinyl esters (REs) from animal sources In thesmall intestine lumen the released REs from digested animalproducts are enzymatically hydrolyzed into retinol and freefatty acids (FFAs) probably by pancreatic lipases esterasesand intestinal phospholipases before being absorbed intoenterocytes with other lipids [14] Inside the enterocytes aportion of retinol is reesterified to REs by the lecithin-retinolacyltransferase (LRAT) or acyl-CoA retinol-acyltransferase(ARAT) REs are packed into chylomicronswith other dietarylipids for the delivery to the rest parts of the body vialymph circulation A small portion of the retinol is directlytransported via portal circulation [15] REs in the plasma andthe liver mainly contain the fatty acyl moieties of palmitateand stearates regardless of the composition of fatty acid (FA)in the diet When triglyceride (TG) is stripped away fromthe chylomicrons by lipoprotein lipase (LPL) REs are stillassociated with chylomicron remnants which are eventuallytaken into hepatocytes In hepatocytes REs are hydrolyzedinto retinol and FFAs again Retinol can be released intothe blood circulation or catabolized into retinal RA andother metabolites for usage or disposal In addition retinolis reesterified into RE again and stored in stellate cells insidethe liver [6]

Provitamin A molecules are from plant sourcesThey are found in colored fruits and vegetables and arenamed carotenoids such as 120573-carotene 120572-carotene and120573-cryptoxanthin [16] Recently with the developmentof transgenic techniques enzymes for the synthesis of120573-carotene have been genetically engineered into the ricegenome [16] The produced rice containing significantamount of 120573-carotene is called golden rice In theory thisrice can be used to provide provitamin A to populationswith low dietary VA availability Carotenoids are convertedinto retinal and then retinol in enterocytes and hepatocytesThe conversion of provitamin A carotenoids to retinalhas two pathways The central cleavage is mediated by120573120573-carotene-15151015840-dioxygenase The eccentric cleavage ismediated by 120573120573-carotene-91015840101015840-oxygenase The resultingretinal is reduced to form retinol [15 17]

REs stored in hepatic stellate cells can be released intohepatocytes again in case of insufficient amount of dietaryVA or provitamin A intake In hepatocytes retinol binds toretinol-binding proteins (RBPs) to form holo-RBPs whichare released into the blood circulation In plasma the holo-RBPs interact with transthyretin (TTR) which binds tothyroxine (T4)This complex transports both retinol and T4Peripheral tissues express RBP receptors such as STRA6 forthe uptake of retinol from plasma [18] Hepatocytes expressRBP4 receptor-2 (RBPR2) which has been considered to beresponsible for plasma retinol homeostasis [19]

13 VA Metabolism VA homeostasis is regulated by a net-work of enzymes and proteins involved in the transportproduction and catabolism of retinoids [20] VArsquos physi-ological functions are mainly mediated by its metabolitesretinal and RA This is achieved via a series of enzymescatalyzing the conversions [21] Two oxidation steps occurduring the conversion from retinol to retinal (retinaldehyde)and then from retinal to RA [22] Retinol is reversiblyconverted into retinal and retinal is irreversibly convertedinto RA [23] Retinol is reversibly oxidized into retinal bytwo families of enzymes alcohol dehydrogenases (ADHs)and retinol dehydrogenases (RDHs) or short-chain dehydro-genasesreductases (SDRs) Two RDHs (RDH2 and RDH10)play major roles in this step in different tissues [24 25]The produced retinal plays important roles in physiologyFor example vision is mediated by 11-cis retinal conjugatedto rhodopsin in response to photon activation Recentlyretinal has been considered an antagonist for the activation ofperoxisome proliferator-activated receptor 120574 (PPAR120574)Whenthe level of retinaldehyde (retinal) was induced in insulin-resistant obob mice after the deletion of Raldh1 gene theirinsulin sensitivity was improved [26]

Retinal is irreversibly oxidized into RA by retinaldehyde(aldehyde) dehydrogenases (RALDHs orALDHs) [21 27 28]Currently four RALDHs (RALDH1 RALDH2 RALDH3and RALDH4) have been cloned and thought to be respon-sible for all-trans or 9-cis RA production in various tissues[29ndash32] They have been collectedly called retinoid dehy-drogenases [21] RALDH1ndash4 proteins were observed in themouse liver based on immunohistochemistry results and theexpression of RALDH1was found in lipid-engorged cells [30]The expression of Raldh1 (also known as Aldh1a1) mRNAwas detected weakly in the rat liver [29] RALDH1 appearsto be the predominant enzyme for RA biosynthesis [33]and elevated RA is observed to control its biosynthesis bydownregulating RALDH1 through modulation of retinoicacid receptor a (RAR120572) and the CCAATenhancer-bindingprotein 120573 (CEBP120573) [34 35] In rat anterior pituitary cellsestrogen receptor alpha can regulate the expression of Raldh1[36]

The expression of RALDH2 and RALDH3 but notRALDH1 can be detected in the developing anterior pituitaryglands of rats [37] The expression of Raldh4 (also known asAldh8a1) mRNA was expressed at high level in the mouseliver [30] Other potential pathways for the RA formationinclude oxidation of retinal by microsomal cytochrome P450

ISRN Hepatology 3

and direct production of RA by cleavage of 120573-carotenein a process that might not involve retinol or retinal asintermediates [38]

In hepatocytes RA can be further modified by enzymessuch as cytochrome P450 26A1 (CYP26A1) to morehydrophilic products [39ndash44] The expression of Cyp26a1mRNA is rapidly induced by RA treatment and is often usedas an indicator of RA production [45]

Other products derived from retinoid metabolism havebeen reported Retroretinoids are a class of retinol derivativesin which the polyene tail is rigidly attached to the 120573-ionone ring by a double bond with the remaining doublebonds retaining the conjugated system and extending it tothe 3 4 double bond within the ring Another bioactiveretinoid is 3 4-dihydroretinol also known as vitamin A2It is abundant in freshwater fish where it is metabolizedinto 11-cis-dehydroretinol which can serve as a ligand forvisual pigments Oxidized retinol metabolites such as 4-oxo-retinoic acid were reported to be highly active indetermining digit development and activation of retinoic acidreceptor 120573 (RAR120573) Some proteins are modified by covalentretinoylation [13]

14 Potential Transcription Factors That Mediate RA EffectsRAR Retinoid X Receptor (RXR) PPAR120573120575 HepatocyteNuclear Factor 4120572 (HNF4120572) and Chicken OvalbuminUpstream Promoter-Transcription Factors (COUP-TFs)

141 Retinoic Acid-Responsive Element (RARE) It has beengenerally believed that the active metabolite of VA RAregulates gene expression through activation of twomembersof nuclear receptors [46] RARs andRXRs [27 28] RARRXRheterodimer or RXRRXRhomodimer associatedwith RAREin the promoters activates the transcription of RA-responsivegenes upon ligand binding [47 48]

RA regulates gene expression through transcription fac-tors bound to RAREs A typical RARE contains two hex-americ motifs 51015840-(AG)G(GT)TCA-31015840 arranged as palin-dromes direct repeats (DRs) or inverted repeats (IRs) [49]These two motifs are separated by nucleotides The commonDRs with 1 2 or 5 nucleotide spacing are termed DR1 DR2and DR5 elements respectively These different DRs maydetermine the regulatory features of the RA-targeted genesWhen bound to DR2 and DR5 elements the 51015840 half-site isoccupied by RXR and the 31015840 half-site by RAR [47] On theother hand the upstream half-site of a DR1 can be recognizedby a RAR a setting that may recruit repressor complexes tosuppress gene expression When bound to DR1 elements thepolarity of the RARRXR heterodimer is inverted and thecomplex is unresponsive to RA stimulation probably dueto the inability of RAR ligands to induce the dissociationof corepressors [50] RXRs can also bind as homodimersto DR1 elements and respond to 9-cis RA By contrast forDR2DR5 elements a RAR occupies the downstream halvesof these RAREs and the complex functions as transcriptionalactivator Additional arrangement of two or three hexamericmotifs with variable spacing has also been identified [51]RARE can be found even in the 31015840 of a gene [52]

142 RARs and RXRs forMediating RAResponses Themajorfunctions of VA are mediated by its active metabolite RA Itis generally believed that all-trans and 9-cis RAs are majorisoforms that mediate the regulation of gene expression [6]However the most important ligand is probably all-transRA as the detection of 9-cis RA produced in a physiologicalsetting has been challenging [6] The RA homeostases iscontrolled by the expression of the enzymes responsible forits production and disposal [53] It is worth noting that somephysiological functions of retinol such as in vision could notbe replaced by RA treatment [54]

RARs and RXRs are members in the nuclear receptorsuperfamily [6 47 55] Nuclear receptors are transcriptionfactors that mediate a complex array of extracellular signalsinto transcriptional responses in a ligand-dependent manner[46] Other members in this family include transcriptionfactors that bind to a variety of physiological activemoleculessuch as endocrine steroids vitamin D thyroid hormone anda large number of ldquoorphanrdquo receptors whose ligands targetgenes and physiological functions were initially unknown[46 56] Upon binding to the ligands nuclear receptorsundergo conformational changes which allow them to inter-act with transcriptional cofactors and in turn regulate theexpression of their target genes [46 57]

RARs and RXRs are widely expressed in metabolic activetissues [58] There are three isoforms each for RARs (RAR120572-120573 and -120574) that bind and respond to all-trans and 9-cis RAsand for RXRs (RXR120572 -120573 and -120574) which can only bind andrespond to 9-cis RA [55] Functional studies have indicatedthat RXRRAR heterodimers act as the main functional unitstransducing RA signals in development which needs theformation of specific heterodimers such as RXR120572RAR120572RXR120572RAR120573 and RXR120572RAR120574 RARRXR heterodimersand RXRRXR homodimers modulate gene expression bybinding to RAREs located in the regulatory regions of theirtarget genes [6 47 55]

Other than RARs many nuclear receptors form het-erodimers with RXRs for binding to their cognate-responsiveelements such as thyroid hormone receptors (TRs) vita-min D3 receptors (VDRs) and PPARs [46] So far RXRsare considered binding partners for other nuclear receptorpathways The activation states of RXRs differ among theseheterodimers and seem to depend on the nature of theirpartners and the binding elements For example in the caseof RARRXR heterodimer either one can be transcriptionallyactive However the ligand-bound RXR is not active unlessits RAR partner binds to a ligand [59] Either PPARs orRXRs in a PPARRXR heterodimer can bind to their agonistsand activate transcription The presence of both ligandsresults in synergistic activation Liver X receptor (LXR)RXRheterodimer retains 9-cis RA responsiveness indicating thatRXR is active upon ligand binding [46] By contrast theTRRXR and VDRRXR heterodimers are thought to benonpermissive as they are activated by the TR ligand tri-iodothyronine (T3) and VDR ligand 125-dihydroxy-VD3(calcitriol) respectively but not by RXR-specific ligands Itis generally believed that in a nonpermissive heterodimerRXR is incapable of binding to its ligands and thus it isoften referred to as a silent partner However recent data

4 ISRN Hepatology

indicated that RXR was able to bind to ligands and leadto dissociation of corepressors from TR thus modulatingheterodimer activity [60]

143 HNF4120572 for Mediating RA Responses Originally HNF-4120572 (NR2A1 gene Nr2a1) was identified as a transcriptionfactor enriched in liver nuclear extract and was responsiblefor transthyretin gene transcription [61] HNF4120572 is a highlyconserved member of the nuclear receptor superfamilyHNF4120572 binds to DNA as a homodimer and acts as a positivetranscriptional regulator of many hepatic genes Expressionof Nr2a1 gene is driven by two distinct promoters the P1promoter that drives expression of splice variants HNF41205721-6in the liver kidney and intestinecolon and the P2 promoterthat drives expression of splice variants HNF41205727-9 in theintestinecolon stomach and 120573-cells of the pancreas Anonsense mutation (Q268X) in exon 7 of the Nr2a1 genethat caused a deletion of 187 C-terminal amino acids of theHNF4120572 protein was indentified in patients with maturity-onset diabetes of the young type I (MODY1) an autosomaldominant early-onset form of noninsulin-dependent dia-betesmellitus (NIDDM) [62]This shortenedHNF4120572 proteinlacks transcriptional activity and fails to dimerize and bind toDNA [63] Another mutation due to a 2 bp deletion in exon3 of the HNF4120572 gene which results in a truncation of theNr2a1 protein to 122 instead of 465 amino acids causes thecarriers to have significantly lower levels of plasma TG andapolipoprotein CIII (apoCIII) than normal subjects [64]

The roles of HNF4120572 have been studied extensively Liver-specific knockout of HNF4120572 resulted in the reduction ofplasma levels of TG and cholesterol accumulation of hepaticlipid contents and decrease of hepatic expression levels ofapolipoproteins AII AIV CII and CIII [65] Moreover ithas been shown that HNF4120572 can activate the expressionof hepatic glucokinase gene (Gck) after it binds to the Gckpromoter [66]

It seems that there is an interaction of PPAR120572 andHNF4120572signaling pathways In the promoter of mouse glycogensynthase 2 gene (Gys2) there are two putative PPAR responseelements (PPREs) one in the upstream promoter and onein intron 1 [67] The DR1 PPRE in the upstream promoterregion is the response element for HNF4120572 The expressionlevel of Gys2 mRNA in the liver of Nr2a1minusminus mice isdramatically lower than that of the wild-type controls Inaddition the Gys2mRNA level in the liver of Pparaminusminusmiceis also lower than that of the wild-type control mice PPAR120572ligand Wy14643 no longer induces Gys2 mRNA expressionin primary hepatocytes of Pparaminusminus mice In Hep2G cellsPPAR120572 activation significantly reduced HNF4120572-dependenttransactivation of Gys2 promoter demonstrating the interac-tion of their signaling pathways [67]

HNF4120572 although initially believed to be an orphanreceptor activity can be modulated by fatty acyl-coenzyme A(CoA) thioesters [68] and also by protein kinase A-mediatedphosphorylation [69] For drosophila HNF4 (dHNF4) regu-lates lipid mobilization and 120573-oxidation [70] Mutant larvaewith dHnf4 deletionwere unable to efficientlymobilize storedfat for energy during starvation consistent with reduced

expression of genes that control lipid catabolism and 120573-oxidation It seems that FAs released from TGs can activatedHNF4 in fasted drosophila which in turn drives FA oxida-tion for energy production [70] This suggests that HNF4120572may be responsive to dietary signals and important in thecontrol of metabolic status

It has been shown that HNF4120572 is responsible for thefunctions of pancreatic 120573-cells The pancreatic 120573-cell-specificNr2a1minusminus knockout mice have impaired glucose-stimulatedinsulin secretion [71] HNF4120572 activates the insulin geneexpression through indirect and direct mechanisms [72]HNF4120572 also regulates the expression of other pancreatic120573-cell genes involved in glucose metabolism and nutrient-induced insulin secretion including glucose transporter-2and liver-type pyruvate kinase [73]

A relationship between RA signaling pathway andHNF4120572 activation has been indicated in the regulation ofthe hepatic gene expression Multiple sites in the promoterof human apoCIII (APOC3) are responsible for positive andnegative regulation of its transcription in HepG2 cells andthe proximal sequence of a 13-nucleotide element for thepositive regulation of the APOC3 transcription is identicalbetween human and rat genomic sequences [74] It has beenshown that different proteins or forms of the same proteinin the nuclear extract from HepG2 and Hela cells bound tothe same 13-nucleotide sequence element in the promoterof the APOC3 gene [75] The activity of this element is notaffected by its orientation in a reporter construct [75] Theproximal hormone-responsive element B (minus87minus72) bindsstrongly to HNF4 ARP1COUP-TFII EAR2COUP-TFIIIEAR3COUP-TFI and RXR120572RAR120572 heterodimers and lessefficiently to homodimers of RAR120572 and heterodimers ofRXR120572with TR120573 or PPAR120572 [76] InHep3B cells the treatmentof RA caused the reduction ofNr2a1mRNA [77] and HNF4120572protein levels after the RA treatment for 3 days [78]

It was found that RA-mediated downregulation of 120572-fetoprotein gene is dependent on the inhibition of HNF1and HNF4120572 in Hep3B cells [77] Since there is no RARE atthe Nr2a1 gene promoter the mechanism for RA-mediatedinhibition of HNF4120572 remains to be investigated On the otherhandHNF4120572 regulates retinoidmetabolism by activating thetranscription of CRBPII gene [79] Furthermore it has beensuggested that HNF4120572 and RXR120572 compete for occupancyof the same site in erythropoietin gene (Epo) promotersequentially regulating its expression during embryogenesis[80] In the development of mouse embryo the hepaticexpression of erythropoietin is sequentially regulated byRARs and HNF4120572 at days E1025 and E1225 respectively[80] This DR2 RARE is in the 31015840 hypoxia-response enhancerof Epo gene and is responsible for RA-mediated inductionof Epo gene in P19 and F9 embryonal carcinomas but not inHep3B cells [81]

144 COUP-TFII for Mediating RA Responses Chicken oval-bumin upstream promoter-transcription factors (COUP-TFs) are members of a family of evolutionarily con-served orphan nuclear receptor without known physio-logical ligand Currently this family has three members

ISRN Hepatology 5

COUP-TFINR2F1ErbA-related protein-3 (EAR3) COUP-TFIINR2F2apolipoprotein-AI regulatory protein-1 (ARP1)and COUP-TFIIINR2F6 (EAR2) [82] COUP-TFs are con-servative among all species with the ligand-binding domainsof COUP-TFI or -II being identical in vertebrates

The cloning and analysis of COUP-TFII (gene NR2F2)cDNA from Hela cells indicate that it is a member ofnuclear receptor superfamily [83] COUP-TFII seems to berequired earlier in the development processes than COUP-TFI COUP-TFII has been thought to suppress gene expres-sion [84] It has been shown to function in a variety of biolog-ical processes such as development cellular differentiationgrowth and metabolic homeostasis [85] Deletion of Nr2f2in mouse is lethal [82] It has been shown that mice withhomozygous deletion of Nr2f2 die at around E10 probablydue to severe hemorrhage and edema and only one-thirdof the heterozygote mice survive before weaning [86] Nr2f2heterozygous pups have growth retardation in comparisonwith their wild-type controls [87] Adult Nr2f2 heterozygousknockout mice have lower body weight and basal plasmainsulin level but higher insulin sensitivity than that of theirwild-type controls [85] They also exhibit resistance to high-fat diet- (HFD-) induced obesity and improved glucosetolerance [85]

COUP-TFII expression can be detected in a variety ofmetabolic active tissues and organs [88] Since heterozygousmice withNr2f2 deletion have improved glucose homeostasisand increased energy expenditure this indicates that COUP-TFII also plays roles in white adipose tissues developmentand energy metabolism [85] COUP-TFII may suppressadipogenesis via inhibiting the expression of genes foradipocyte differentiation such as the expression of sterolregulatory element-binding protein-1c (SREBP1c) PPAR120574and CCAATenhancer-binding protein 120572 (CEBP120572) [89]COUP-TFII regulates the expression of insulin gene andseveral other genes involved in glucose and lipid metabolismin pancreatic 120573-cells Heterozygous mice with Nr2f2 deletionin pancreatic 120573-cells have impaired glucose sensitivity andabnormal insulin secretion [90]

COUP-TFII regulates gene expression via both protein-protein and protein-DNA interactions [76] For exampleCOUP-TFII binds to hormone response elements (HREs)recognized by other nuclear receptors and in turnmodulatesthe expression of these genes It has been shown that COUP-TFII can bind to a variety of HREs that contain direct orinverted imperfect AGGTCA repeats with various spacesCOUP-TFII can also interact with the common partners orgeneral transcriptional factors to modulate gene expression[84 91] For example the amount of RXR available for theformation of high-affinity DNA-binding complexes of thethyroid hormoneRAR subfamily can be limited COUP-TFIIcan also actively silence basal and activated transcriptionlikely through direct interaction with TFIIB or other generaltranscription factors [84]Therefore COUP-TFII may antag-onize the functions of other hormones and in turn alter thecellular responses to multiple-hormone signaling pathwaysand it can have profound effects on metabolic homeostasis

COUP-TF protein interacts with RXR120572 to form het-erodimer [92] Using RXR120572 cDNA probe COUP-TFs were

identified to bind to RAREs The original COUP-TF-bindingsite in the ovalbumin gene is also a RARE that is repressedby COUP-TF [93] On the other hand RXR120572 and COUP-TFII can bind to the same DR1 element individually or inthe heterodimeric form in an electrophoresis mobility shiftassay (EMSA) Cotransfection of COUP-TFII and RXR120572suppresses RXR-mediated activation of CRBPII promoterwhich contains one RARE [92] COUP-TFs are involved inthe modulation of RAR- and RXR-mediated responses toretinoids during embryogenesis [84] Recently COUP-TFIIhas been identified as a low-affinity RA receptor The ligandbinding of COUP-TFII is in an autorepressed conformationAt high concentrations RA is able to promote COUP-TFIIto recruit coactivators and to activate a COUP-TF reporterconstruct [94] These observations suggest a linkage betweenRA and COUP-TFII signaling pathways

145 PPAR120573120575 forMediating RAResponses PPARs aremem-bers of nuclear receptor superfamily They take part in theregulation of a variety of physiological functions such as celldifferentiation metabolism and immune functions [95] Sofar three PPAR isoforms PPAR120572 PPAR120573120575 and PPAR120574are identified and reported The expression of PPAR120573120575 isubiquitous which can be detected in a lot of cell typesand tissues [96 97] In rats PPAR120573120575 mRNA and proteinsare expressed ubiquitously and often coexpressed with otherPPARs [98] Similar expression profiles are observed inmice [99ndash101] In mice PPAR120573120575 protein can be detectedin a variety of tissues with high expression levels in thesmall intestine skin and liver [102] The expression levels ofPPAR120573120575mRNA and protein in the liver of rats fasted for 12hours are reduced and increased upon refeeding for 45 hours[103]The expression of low levels of human PPAR120573120575mRNAcan be detected in the adipose tissues the skeletal muscle theliver the kidney and the intestines [104]

It has been shown that RA is a high-affinity ligand(nanomolar range) for PPAR120573120575 activation in COS-7 cells[105] RA-mediated activation of PPAR120573120575 plays a role incell proliferation [106] In certain types of cells RA isrespectively delivered to RAR and PPAR120573120575 by cytosolretinoic acid-binding protein II (CRABP-II) and fatty acid-binding protein 5 [107] The activation of these two receptorsby RA has opposite effects on cell growth RA can activatePPAR120573120575 in preadipocytes and mature adipocytes [108 109]RA treatment prevents obesity development in diet-inducedobesity (DIO) via increase of lipolysis [108] and inhibition ofadipocyte differentiation [109]

However when human PPAR120573120575 was stably over-expressed in human keratinocyte cells no change inPPAR120573120575 target gene expression could be observed after thetreatment of RA [110] Many studies have shown that endo-cannabinoids regulate the activity of PPARs via direct andindirect mechanisms [111] The expression of endocannabi-noid receptor type 1 (CB1) is reduced upon overexpressionof PPAR120573120575 suggesting other pathways that PPAR120573120575 isinvolved in [112]

In summary retinol in hepatocytes can be either storedas REs or oxidized into retinal as shown in Figure 1 RA

6 ISRN Hepatology

HepatocyteCell membrane

RE Retinol Retinal RA

Other metabolic pathwaysNuclear

membrane

Cytosol RAOther ligands

RARRXR PPAR120573120575

COUP-TFII UpdownmRNAHNF4120572HNF4120572

RARE

Nucleus

Figure 1 The effects of RA production and other metabolicfactors on the activities of transcription factors associated with aretinoic acid-responsive element (RARE) in the promoter of anRA-targeted gene In primary hepatocytes RA is produced fromretinal derived from retinol Retinol can be esterified into retinylester (RE) or oxidized into retinal The RARE can be occupied byretinoic acid receptor (RAR) retinoid X receptor (RXR) hepatocytenuclear factor 4120572 (HNF4120572) chicken ovalbumin upstreampromoter-transcription factor II (COUP-TFII) and peroxisome proliferator-activated receptor 120573120575 (PPAR120573120575) in the forms of heterodimers orhomodimers These transcription factors receive signals from RAand metabolic pathways and regulate the expression of the RA-responsive gene

is dynamically produced and sent to nucleus where itinteracts with transcription factors associated with RAREin the enhancer regions of the RA-responsive genes Sofar the transcription factors that can be associated with aparticular RARE include RAR RXR COUP-TFII HNF4120572and PPAR120573120575 They form heterodimers or homodimers andbind to RARE to regulate the transcription rate of that geneThe nuclear receptors that occupy the RARE at any givenmoment may be determined by the VA status of the animaland the developmental differentiation and metabolic statesof hepatocytes These transcription factors integrate signalsfrom RA and other metabolic pathways to control the geneexpression positively and negatively Other metabolic signalsin combination with RA may affect the occupancy of thenuclear receptors bound to the RARE and their activationsand may in turn alter the outcomes of the RA-mediatedtranscription responses

2 VArsquos Roles in Glucose Metabolism

As a convenient energy source glucose can be used by all cellsthat are in charge of different physiological functionsGlucoseis metabolized differently in response to hormonal and nutri-tional statuses [113] Hepatocytes utilize and produce glucosedepending on the physiological needs and feeding status ofa subject These processes are regulated by nutritional andhormonal stimuli VA status has been implied to play a role

21 The Effects of VA Status on Hepatic Glycogen ContentsThe roles of VA in glucose metabolism had been suggestedIn 1937 the liver samples of patients who died of diabetesshowed an elevation of VA contents [114] When rats werefed a VA-deficient (VAD) diet to induce VA deficiency theirliver glycogen content was depleted [115] Since VA deficiencyalso caused reduction of food intake in the VAD rats a pair-feeding control group was included The pair-fed rats withequal energy intake as that of VAD rats had higher hepaticglycogen content [115] This depletion of hepatic glycogencontent was attributed to the reduction of glycogenesisfrom trioses rather than directly from glucose [115] Thephenomenon of the depletion of hepatic glycogen contentin the liver of VAD rats has also been observed recently inmy lab [116] On the other hand when rats were fed a dietwith excessive amounts of VA for two days an elevation ofthe hepatic glycogen content in the liver after fasting wasobserved [117] It seems that hepatic VA content is directlycorrelated with the hepatic glycogen content

22 The Effects of Animal VA Statuses and Retinoids onHepatic Gck Expression To initiate the hepatic glucose uti-lization glucose is phosphorylated into glucose 6-phosphateby hexokinases in the first reaction of glycolysis So far fourhexokinase isozymes hexokinase I (A) II (B) III (C) andIV (D) have been identified They have different tissue dis-tributions intracellular locations and kinetic characteristicsMammalian hexokinase IV (D) is also known as glucokinase(GK) (ATP d-hexose 6-phosphotransferase EC 2711) [118ndash121] Mutations of GK have been associated with MODY[122] GK has two unique features that differentiate it fromother hexokinase family members It has low affinity forglucose (higher Km) and it is insensitive to allosteric inhi-bition mediated by physiological concentrations of glucose6-phosphate whereas other hexokinases are sensitive to it[118 121 123 124] In addition to glucose other substrates ofGK include fructose mannose and 2-deoxyglucose [118]

Generally GK activity is mainly observed in the liverand pancreatic islets The 120573-cells and liver GK isoforms havesimilar kinetic properties [125 126] In the short term theGK activity can be regulated via allosteric interactions andcovalent modifications such as binding to GK regulatoryprotein [127] phosphorylation by protein kinase A [128] andinteractionwith a cytosolic GK-associated phosphatase [129]

The long-term regulation of GK activity is done throughthe transcription of its gene Gck which is differentiallyregulated by an upstream promoter in pancreatic 120573-cells anda downstream promoter in hepatocytes [130 131] Using astrain of transgenic mice containing the cDNA of humangrowth hormone gene driven by an upstream Gck promoterfragmentGck expression has been found in certain neuroen-docrine cells of the pancreas pituitary brain gut thyroidand lungs [132] Activation of the upstream or downstreampromoter leads to the generation of a Gck mRNA with aunique 51015840 sequence derived from exon 1120573 or 1L respectivelySince the translation initiation coden is located in the firstexon the GK proteins encoded by the different transcriptsdiffer in the first 15 amino acids at the amino terminus

ISRN Hepatology 7

[130 131] The mechanisms by which the upstream and thedownstream promoters are selectively activated in differentcells have not been revealedThe temporal and special controlof the promoter selectionmust be determined by signals fromdifferentiation and development processes

The upstream and downstream promoters are activatedbased on the hormonal and nutritional conditions of thesubject For example the hepatic but not the pancreatic 120573-cell Gck expression is reduced while fasting and increasedwhile refeeding [130] In the rat liver insulin and glucagonrespectively induce and inhibit the expression of GckmRNA[133ndash135] A long-standing question in the field is the insulin-responsive element (IRE) responsible for the insulin-inducedhepaticGck expression Using the reporter gene constructs tostudy insulin-induced Gck promoter activation has not beensuccessful For example a reporter gene construct containinga fragment of 55 kb hepatic Gck promoter failed to showany response to insulin treatment in rat primary hepatocytes[136] This suggests that the IRE of the hepatic Gck mightbe in an area not included in this 55 kb promoter fragmentAlternatively the unresponsiveness to insulin of the reportergene constructs in the experimental settings could be due tothe short-lived signal from insulin for Gck transcription aswe have shownpreviously [137] Interestingly the hepatocyte-specific enhancer region that controls the activation of liver-specific promoter has been located in the region from minus1003to minus707 relative to the transcription initiation site in primaryrat hepatocytes By contrast this region acts as a silencer inFTO-2B hepatoma cells and has no effects on insulinomacells [138] Further studies are needed to identify the insulin-responsive element in the hepatic Gck promoter

The direct effects of RA on the expression of Gck mRNAin primary rat hepatocytes have been studied Previouslyothers have shown that all-trans RA induced Gck expressionin primary rat hepatocytes However nonadditive effect ofRA on insulin-induced Gck expression was observed [139140] Recently we have shown that retinoids synergized withinsulin to induce Gck expression in primary rat hepatocytes[137] We have observed that all-trans retinol retinal and RAare able to synergize with insulin to induce Gck expressionprobably via the activation of RARRXR in primary rat hepa-tocytes In addition VA status also controls the expression ofhepatic Gck expression [137] The levels of Gck mRNA [116]and its activity [137] in the liver of VAD rats are lower thanthose of VA-sufficient (VAS) controls In addition a singletreatment of RA increases the hepatic Gck expression in rats[137]

23 The Effects of Animal VA Status and Retinoids onPck1 Gene Expression The plasma glucose homeostasis isachieved through its dietary intake and production fromendogenous noncarbohydrate sources During fasting glu-cose is generated via gluconeogenesis The cytosolic form ofphosphoenolpyruvate carboxykinase (PEPCK-C EC41132)which catalyzes the conversion of oxaloacetate into phos-phoenolpyruvate in the presence of GTP [141] has beenconsidered to be the first rate-limiting enzyme of gluconeoge-nesisThe expression of PEPCK-C gene (Pck1) and its activity

have been detected in the liver kidney adipose tissues andsome other tissues [141ndash143] Other than gluconeogenesisPEPCK-C activity has been considered to be responsible forglyceroneogenesis and cataplerosis [144] Since no allostericregulator of PEPCK-C has been identified its activity isprimarily controlled by the level of Pck1mRNA [141ndash143]

The transcription of hepatic Pck1 is regulated by hor-monal and nutritional stimuli In the liver fasting diabetescarbohydrate-free diets and high-fat diets increase Pck1 geneexpression whereas refeeding insulin treatment and high-carbohydrate diets decrease Pck1 gene expression Glucagonglucocorticoids thyroid hormone and RA induce hepaticPck1 expression while insulin and glucose inhibit it [145]

The transcription regulation of Pck1 has been studiedextensively [142 143] The protein-binding sites at the prox-imal region of rat Pck1 promoter have been determined byDNase I footprinting assays [146 147] Multiple regulatoryelements including distal proximal cyclic AMP-responsiveelement (CRE) [148] have been identified Proteins in ratliver nuclear extracts can interact with the two CREs andsix additional binding sites (P1 to 6) [142] The transcrip-tion factors that bind to these sites include HNF4120572 [149]glucocorticoid receptor [148 150ndash153] RAR [154ndash157] TR[154 158] LXR [159] COUP-TF [149] the Forkhead familyof transcription factors [160] CEBP and cAMP regulatoryelement-binding (CREB) protein [161] and SREBP-1c [162163] Additionally transcription coactivators such as CREB-binding protein (CBP) [164] steroid receptor coactivator 1(SRC1) [165] and peroxisome proliferator-activated receptorgamma coactivator-1-alpha (PGC-1120572) [166] also participatein the regulation of hepatic Pck1 gene expression

Using reporter gene assays and hepatoma cells twoRAREs have been identified in the hepatic Pck1 promoter[154 155 167]WhenPEPCKbovine growth hormone (bGH)transgenic mouse strains are used VA deficiency causes thereduction of the transgenersquos transcription [167]The RARE1 isconsidered to be important for mediating the RA-regulatedPck1 expression in the mouse liver [157] In mice VA statusaffects the association of RNApolymerase II and histone codeof Pck1 promoter [168 169] Later on these RAREs have beenshown to bind toHNF4120572 RXR120572 RAR120572 PPAR120572 and COUP-TFII [170]

In an attempt to study the lipophilic molecules that affectinsulin-regulated gene expression in primary rat hepatocyteswe have obtained lipophilic extract (LE) from the rat liverMyoriginal study has shown that this LE induces Pck1 expressionand attenuates insulin-mediated suppression of Pck1 tran-scription in primary rat hepatocytes [171] Interestingly thesame LE synergizes with insulin to induce Gck expression inthe same cells [137]The activemolecules in the LE are retinoland retinal [137] We have shown that retinol retinal andRA all can affect insulin-suppressed Pck1 expression [172]In rat primary hepatocytes the proximal one of the twoRAREs in the rat Pck1 promoter [154ndash156] is responsiblefor mediating the retinoid effects [172] The expression ofhepatic Pck1mRNA in rats seems to respond to VA deficiencydifferently from that in mice We have shown that the hepaticPck1mRNA level in the Zucker lean (ZL) rats is not reduced

8 ISRN Hepatology

Hepatocyte

Induction

Induction

Induction

1 2

Gck

Pck1

Cell membraneCytosol

RA RA

RARESynergy

Signalcascade Insulin

AttenuationNuclear

membrane NucleusRAREs

Inhibitio

n

Figure 2 RA synergizes with insulin to induce Gck expressionand attenuates insulin-suppressed Pck1 expression RA inducesthe expression levels of Gck and Pck1 via the activation of bothRARRXR (the oval dimmers on the RAREs) in the absenceof insulin Insulin alone stimulates the expression of Gck andsuppresses the expression of Pck1 In the presence of both insulinand RA the expression of Gck is further increased (synergy) Onthe other hand the insulin-mediated suppression of Pck1 expressionis attenuated This is because RA still induces Pck1 expressionvia activation of RAR in the presence of insulin Therefore Pck1transcript level in the RA + insulin group is higher than that in theinsulin group (attenuation)

in VA-deficient state [116] VA deficiency only reduces thehepatic Pck1mRNA in the Zucker fatty (ZF) rats [116]

It is important to note that the respective activities of GKand PEPCK-C are induced in different physiological condi-tions For example insulin induces Gck and suppresses Pck1expression as shown in Figure 2 In primary rat hepatocytesactivation of either RARs or RXRs by RA is sufficient toinduce the expression of both Pck1 [172] and Gck [137] How-ever activation of RAR potentiates (for the insulin-mediatedinduction of Gck expression) and attenuates (for the insulin-mediated suppression of Pck1 expression) insulin actionsat the same time in the same hepatocytes For Gck RA-mediated activation of RARs and RXRs can be potentiated byinsulin [137] which results in the synergy For Pck1 only RA-activated RXRs but not RARs are inhibited by insulin whichresults in the attenuation [172] This causes the production ofmore Pck1 mRNA in the presence of RA than in the absenceof it even in the insulin-suppressed state It indicates that themechanisms of RA-mediated activation of RARs and RXRsprobably depend on the promoter context or the isoformsassociated with the promoters of their downstream genesin the presence of insulin Therefore the roles of retinoidsin hepatic glucose metabolism deserve further investigationespecially the roles of the interactions between retinoidsand insulin signaling pathways in the regulation of genetranscription

24 Role of RBP4 in Insulin Resistance Plasma VA is boundto RBP4 which is mainly produced in the liver [13] TheRbp4 mRNA is also expressed to a certain extent in adipose

tissues and kidney [13] In the plasma retinol-RBP4 complexis associated with transthyretin (TTR) a process to increasethe size of the holo-RBP4-TTR complex to reduce the lossduring renal filtration [173]

Recently the plasma RBP4 has been suggested to playroles in metabolic homeostasis It has been reported thatinsulin-resistant human subjects and animals have higherplasma RBP4 levels than normal ones due to its elevatedproduction from adipose tissues [174] In mice RBP4administration has been shown to reduce insulin sensitivityand increase the expression levels of hepatic gluconeogenicgenes such as Pck1 and the catalytic subunit of glucose 6-phosphatase (G6pc) [175] Additionally reduction of plasmaretinol and RBP levels has been reported in type 1 diabeticpatients [176] and in streptozotocin- (STZ-) induced diabeticrats [177] Rbp4 knockout mice have improved insulin sen-sitivity [175] The treatment fenretinide a synthetic retinoidderivative that disrupts the association of RBP4 and TTRimproves insulin sensitivity in HFD-induced obese mice[175]

When a compound specifically developed to disrupt theRBP4 and TTR interaction was used to treat mice it suc-cessfully disrupted the formation of RBP4-TTR complex andcaused the reduction of plasma RBP4 level [178] Howeverthe reduction of plasma RBP4 level did not result in animprovement of insulin sensitivity [178] In addition theimprovement of insulin sensitivity in Rbp4 knockout micecould not be observed in this study [178] Therefore the ele-vation of insulin sensitivity in mice treated with fenretinideis probably due to a mechanism other than the disruption ofRBP-TTR complex and reduction of plasma RBP4 levels

3 Roles of VA in FA and TG Metabolism

FAs are needed for many aspects of cellular functions fromsignal transduction to energy production The continuoussurvival of a given cell depends on the constant energysupplies from the environment or storage sources Thestorage of FA in the form of TG ensures the constant energysupply in a cell or organism for a prolonged period oftime when environment energy is limited In animals thehomeostasis of FA and TG is dynamically regulated by theliver and the adipose tissues in response to nutritional andhormonal stimuli [179 180] During fasting or starvation FAsare released from adipose depots after lipolysis and oxidizedin the liver and muscle for energy production [181] Afterrefeeding dietary and newly synthesized FAs are convertedto TGs for the storage in the adipose tissues [182] On theother hand the altered regulation of this system may causeproblems For example the excessive synthesis and storage ofFAs in the form of TGs can cause the development of obesityand other metabolic diseases

31 The Effects of VA Status on the Body Fat and Plasma LipidProfile VA was first recognized as a dietary lipophilic factorwhich was essential to support the normal growth of labanimals [3 4] Subsequently it was observed that along withthe reduction of body mass the VAD rats that had been fed

ISRN Hepatology 9

aVADdiet at weaning (21 days old) formore than 9weeks hadreduction of carcass fat but not cholesterol content [183] Onthe other hand this reduction of body fat was not observedin the rats of the pair-feeding group which were given thesame amount of a VAS diet in weight and calories as theone consumed by the VAD rats [183] These results indicatethat the reduction of food intake alone could not be used toexplain the depletion of body fat in the VAD rats

The VA status also seems to affect the hepatic expressionof apo AI mRNA The expression of hepatic apo AI hasbeen shown to be sensitive to VA status [184] When theLewis strain rats develop VA deficiency the expression levelof hepatic but not intestinal apo AI mRNA is elevated Thisinduction is dropped upon single dosage of RA treatment[184] On the other hand in the intestine and liver of VA-deficient Wistar rats both all-trans RA and 9-cis RA caninduce apo AI mRNA levels [185] The same treatment canonly induce the mRNA level of apo CIII in the intestine butnot in the liver [185] In humans the plasma VA levels arepositively correlated with the elevations of proteins of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiapatients [186]

When male Wistar rats were fed a VAD diet for 3 monthsafter weaning (21 days old) they had lower plasma TGs andcholesterol levels than the control ones fed a VAS diet [187]When the hepatic synthesis of FAs and phospholipids wasanalyzed in the liver slices the incorporations of [14C]cholineinto phosphatidylcholine and [14C]acetate into FAs were alsoreduced in the VAD rats compared with their VAS controls[187] The VAD rats had lower activities and mRNA levels ofacetyl-CoA carboxylase but higher activity and mRNA levelof carnitine palmitoyltransferase-I than VAS rats had [187]These results demonstrate that there is a reduction of hepaticfatty acid synthesis along with an induction of hepatic fattyacid oxidation in the liver of VAD rats

My lab has conducted experiments and shown that VAstatus affects the obesity development in ZF rats and controlsplasma TG levels in ZL and ZF rats [116] ZF rats a ratmodel of obesity development [188] develop obesity dueto a missense mutation in the extracellular domain of allleptin receptor isoforms [189ndash191] They have been used forthe studies of obesity insulin resistance and other aspectsof metabolic diseases [192 193] We have analyzed growthplasma parameters and expression levels of hepatic genes ofmale ZL and ZF rats fed a VAD or a VAS diet at weaning(21 days of age) for 8 weeks Body masses of ZL and ZF ratsfed the VAD diet are lower than those of their correspondingcontrols fed the VAS diet at the end of the feeding periodThe VAD ZL or ZF rats begin to take less food than the VASones after five weeks on the diet The VAD ZL or ZF rats havelower plasma glucose TG insulin and leptin levels than theircorresponding VAS rats have The liver glycogen content netweights of epididymal fat and liver and fat-to-body massratio (ZL only) in the VAD rats are also lower than those inthe VAS ones [116] This demonstrates that VA status affectsplasma TG levels in both ZF and ZL rats and the obesitydevelopment in ZF rats This phenomenon may be caused by

the combination of VA deficiency and hypoinsulinemia sinceinsulin secretion is impaired in the VAD rats [194]

32 The Development of Hypertriglyceridemia inPatients Receiving Retinoic Acid-Based Treatments

321 The Uses of RA-Based Medicines in Clinic RA-basedmedicines tretinoin (all-trans RA) isotretinoin (13-cis RA)and alitretinoin (9-cis RA) have been used in clinic to treatdiseases such as acute promyelocytic leukemia and skindisorders [11] In fact isotretinoin has been widely used totreat severe acne Early clinical observations indicate that themedical use of isotretinoin in human subjects results in theelevation of their plasma TG levels [195ndash197] A significantportion of patients with acne receiving isotretinoin treatmentdeveloped hypertriglyceridemia [9 10] In addition thesystemic administration of isotretinoin in patients with acneresulted in the elevation of plasma levels of alanine amino-transferase (ALT) and aspartate aminotransferase (AST)indicating the liver damage [198]The hypertriglyceridemia isalso associated with reduced insulin sensitivity and elevatedTG in the very-low-density lipoprotein (VLDL) fraction[195] The treatment of all-trans RA resulted in body massgain and hypertriglyceridemia in patients with acute promye-locytic leukemia [199 200] Moreover RA treatment alsoraises plasma TG levels in rats [201ndash203]

322 The Mechanism of RA-Mediated Hypertriglyceridemiain Patients Apo CIII is produced from liver and consideredan inhibitor of LPL activity [204] Mice with Apoc3 geneknockout have hypotriglyceridemia and enhanced in vivoVLDL-TG clearance [205] On the other hand transgenicmice with overexpression of apo CIII develop hypertriglyc-eridemia [206] The RA-induced hypertriglyceridemia hasbeen attributed to RA-induced apo CIII expression

In healthy human subjects isotretinoin treatment causesa rise of plasma apo CIII protein level [207]This is caused bythe induction of Apoc3 mRNA via the activation of RXR ata RARE in its promoter [207] The plasma TG levels in ratstreated with RXR-specific agonist (LG100268) are inducedrapidly and constantly [208] This results in the reducedactivity of LPL in the heart and skeletal muscle of thoseanimals [208] The RARE is identified in the C3P regionwhich controls the hepatic specific expression of Apoc3 gene[75] Interestingly the same site is also considered to beresponsible for mediating the effects of HNF4120572 and COUP-TFII onApoc3 gene expression [209]The expression ofApoc3seems to be regulated differently by the C3P-binding proteins[75]

It is worth to note that insulin suppresses Apoc3 mRNAexpression in STZ-induced diabetic mice [210] In additionthe activation of RXR by LG100268 treatment induces insulinsensitivity and reduces TG levels in obese and diabetic mice[211] The understanding of the regulatory mechanism thatintegrates hormonal and nutritional signals at the regulatorysites such as C3P in Apoc3 promoter will shed some lightson the regulation of hepatic lipid homeostasis It will also

10 ISRN Hepatology

provide a novel target for the treatment of the RA-inducedhypertriglyeridemia

323 The Effects of RA Treatment on Obesity Developmentin Mice Interestingly the RA administration in rodentscauses reduction of body mass as summarized in [212] Thiskind of reduction of body mass has been associated withenhancement of insulin sensitivity in genetic [213] or DIOmice [108] The mechanisms of RA-mediated attenuation ofinsulin resistance have been thought to be the induction ofenergy expenditure through PPAR120573120575 activation [108] andthe inhibition of adipogenesis throughRXR120574 activation [109]On the other hand retinol can be metabolized in adipose tis-sues [214]Themice with deletion ofRaldh1 gene (Raldh1minusminus)have elevated retinal in their adipose tissues and are resistantto diet-induced obesity and insulin resistance [26] This hasbeen attributed to the suppression of adipogenesis by retinal-inhibited activation of PPAR120574 and RXR [26] It is interestingto note that either retinal or RA can inhibit the adipogenesisand cause the improvement of insulin sensitivity in micebased on these studies

33 Roles of VA and Retinoids in the Regulation of HepaticLipogenic Gene Expression Insulin resistance diabetes andother metabolic abnormalities are associated with profoundchanges of hepatic lipid and glucose metabolismThis can beattributed at least in part to the altered expression of genesinvolved in glucose and lipid metabolism [215] The hepaticlipogenesis contributes to the homeostasis of FAs and TGs

331 The Regulation of Hepatic Srebp-1c Expression by VAStatus and Retinoids Treatment Insulin plays an essentialrole in the hepatic FA synthesis It has been known for a whilethat insulin is needed for the glucose usage for lipogenesis andCO2production in the liver [216] The hepatic FA synthesis

rises sharply and continuously after rats are fasted and thenrefed a high-carbohydrate diet [217] The amount of fattyacid synthase (FAS) is induced in normal rats refed a high-carbohydrate diet after fasting and in STZ-induced diabeticrats after insulin administration [218] In the insulin-deficientrats the induction of FAS after refeeding occurs only wheninsulin injection is injected [219] a process attributed to theinduction of FAS gene (Fas) [220 221]

The transcription of hepatic Fas is controlled by a tran-scription factor named SREBP-1c [222] In the liver-specificSrebp-1c knockoutmouse liver the induction of Fas and otherlipogenic genes by refeeding after fasting is blunted [223]Interestingly insulin also specifically induces the Srebp-1cexpression in the liver [224] via two liver X receptor elements(LXREs) and one sterol-responsive element (SRE) [225]However in liver-specific insulin receptor knockoutmice theinduction of hepatic Srebp-1c by refeeding largely remainedunchanged [226] This suggests that nutrient-derived signalsmay activate downstream of insulin receptor signaling path-way to regulate Srebp-1c expression and hepatic lipogenesis[226]

As stated in the previous section my research group hasobserved that the VAD ZL and ZF rats have lower plasma TG

levels than their VAS controls [116] This is accompanied bythe reduction of the hepatic expression of Srebp-1cmRNA inVA-deficient animals [116] My research group has reportedfor the first time that retinoids synergize with insulin toinduce the expression of Srebp-1c in primary rat hepatocytes[227] Further analysis of the Srebp-1c promoter reveals thatthe previous identified LXREs responsible for mediatinginsulin-induced Srebp-1c expression are also RAREs [227]These observations show that retinoids (nutritional) andinsulin (hormonal) signals converge to regulate the FAsynthesis in the liver

332 The Effects of VA Catabolism on the Regulation of Srebp-1c Expression in Primary Rat Hepatocytes More recentlyretinoids have been proposed to play roles in glucose and lipidmetabolism and to maintain energy homeostasis [228 229]VA (retinol) is reversibly converted into retinal and retinalis irreversibly converted into RA [23] Retinal the precursorof RA production is able to synergize with insulin to inducethe Srebp-1c expression in primary rat hepatocytes [227]This suggests that the dynamic production of RA influencesthe expression of hepatic lipogenic genes It has led us toinvestigate the roles of RA production in the insulin-resistantanimals

In the liver of the Raldh1minusminus mice RA production isreduced in response to a load of retinol [230] The Raldh1minusminusmice are resistant to the development of obesity and insulinresistance after being fed an HFD [26] This is attributed tothe elevation of retinal content due to the lack of conversionof retinal to RA in the adipose tissues of the Raldh1minusminusmice Additionally the liver of the Raldh1minusminus mice hasaltered regulation of the genes for gluconeogenesis andsignificantly attenuated hepatic TG synthesis indicating theimportant role of hepatic VAmetabolism in glucose and lipidhomeostasis [231]

The hepatic expression levels of RALDH1 and RALDH2are induced in mice fed a high-cholesterol diet [232] SREsare located in the promoters of these two genes whichare induced by SREBP-1c overexpression The expression ofSrebp-1c is induced by the oxysterols derived from the high-cholesterol diet [232] This research work demonstrates theinteraction of cholesterol and RA metabolism in the liver Inaddition it has been shown that the level of Raldh1mRNA iselevated in the kidney of dbdb mice [233] Both dbdb miceand ZF rats develop obesity due to the mutation of leptinreceptor [234]

In an attempt to understand the roles of VA metabolismin the states of metabolic diseases we have compared theexpression levels of enzymes responsible for the productionof retinal and RA in the freshly isolated and cultured primaryhepatocytes from ZL rats and ZF rats [45] We have foundthat in the primary rat hepatocytes the enzymes responsiblefor the conversions of retinol to retinal and from retinal toRA are most likely RDH2 and RALDH1 respectively Theexpression levels of Raldh1 mRNA and its protein are higherin hepatocytes from ZF rats than in those from ZL rats[45] When overexpressed RALDH1 introduces the retinal-mediated induction of Srebp-1c in INS-1 cells which do not

ISRN Hepatology 11

respond to retinal in our previous study [227] These resultsindicate that insulin-resistant animals such as ZF rats mayhave alterations in retinoids metabolism

Thus we have hypothesized that the change of RAproduction from the oversupply of dietary VA due to thehyperphagia of ZF rats results in higher Srebp-1c expressionin ZF hepatocytes [45] The elevated SREBP-1c expressioncan further induceRaldh1 expression to create a feed-forwardmechanism that could be one of the reasons responsible forthe increased lipogenesis in the liver of ZF rats All of theseobservations indicate the potential roles of RA metabolismin the development of obesity and insulin resistance whichdeserves to be further studied

4 VArsquos Roles in Mediating Hepatic InsulinAction and Insulin Resistance

41 Insulin and Its Signal Transduction The insulin moleculeis made of two chains linked by one intra- and one interchaindisulfide bonds [235] The insulin receptor is a transmem-brane and heterotetramer tyrosine kinase receptor (two 120572and two 120573 subunits) linked by disulfide bonds as well [236]The binding of insulin to its receptor causes conformationchanges and transphosphorylation of the 120573-subunit tyrosinekinase [237 238] which initiates the signal transduction[239] Protein-protein interactions are involved in the trans-duction of insulin signalThe signal is transduced bymultiplecomponents in a complex network containing cascades ofkinases and phosphatases [240 241] The first intracellularcomponents mediating insulin signals are insulin recep-tor substrates (IRSs) protein molecules phosphorylated byinsulin receptor 120573-subunit and mediating insulin signals[242]

The insulin signal event is further amplified byphosphatidylinositide 3-kinases (PI3K)protein kinaseB (PKBAkt) pathway and GRB2mitogen-activated proteinkinase (MAPK) pathway [243ndash245] Another serinethre-onine kinase that can be activated by PI3K is the atypicalprotein kinase C [246] Human liver expresses severalprotein-tyrosine phosphatases (PTPs) [247] Okadai acid aninhibitor of protein phosphatase type 2A and type 1 inhibitsglycogen synthesis and insulin-stimulated Gck expression inprimary rat hepatocytes indicating that dephosphorylationmechanism may also participate in mediating insulinsignaling [248] These components are shared by insulin-likegrowth factor (IGF) receptor and involved in mediatinginsulin and IGF signals [249]

42 Metabolic Diseases and Insulin Resistance The rise ofthe number of people with one or more metabolic diseasessuch as obesity and diabetes in the world has become apublic health problem [250] The interactions of genetic andenvironmentalnutritional factors may be responsible for thecurrent rise of metabolic diseases The long evolutionaryprocess has equipped human and animal bodieswith a varietyof regulatory mechanisms controlling these interactions [251252] Human diets contain not only energy derived frommacronutrients but also micronutrients and other factors

which may influence the metabolic outcomes The roles ofindividual micronutrients in the development of metabolicdiseases are still unrevealed

One common property of human obesity and NIDDMis insulin resistance in which a given amount of insulinproduces less than normal physiological responses Dietaryfactors and manipulations have been considered to play arole in the development of insulin resistance in humans andanimals For example feeding an HFD to young and insulin-sensitive subjects for two days causes the development ofglucose intolerance [253] In the skeletal muscle of rats fedan HFD for 8 weeks the insulin-induced glucose uptakeis impaired [254] FFAs have been considered the factorsresponsible for HFD-induced leptin and insulin resistance[255ndash257]

43 Hepatic Insulin Resistance and Vicious Cycle The liverplays an essential role in the control of glucose andlipid homeostasis It coordinately regulates the processesin responses to nutritional and hormonal stimuli Insulinplays a major role in directing the liverrsquos metabolic status[258] which is partially attributed to the regulation of theexpression of genes involved in hepatic glucose and lipidmetabolism [215 259]

Insulin controls the expression of a variety of genesinvolved in glycolysis glycogenesis and lipogenesis andgluconeogenesis in the liver [145] Generally hepatic lipidand glucose metabolism is altered with the development ofinsulin resistance in obesity and NIDDM [258] This canbe reflected in the expression of insulin-regulated hepaticgenes for glucose and FA metabolism When the liver isinsulin sensitive insulin stimulates lipogenesis and inhibitsgluconeogenesis For example to regulate hepatic glucosehomeostasis insulin increases the expression of Gck gene[119 120] and Srebp-1c [224] a family member of SREBPswhich regulate the hepatic cholesterol and FA biosynthesisand their homeostasis [260] It suppresses the expressionof Pck1 [142] and G6pc [145] which control the first andlast steps of gluconeogenesis respectively When the liver isinsulin resistant insulin no longer inhibits gluconeogenesisHowever the liver still keeps the elevated lipogenesis Theelevated FA biosynthesis in the insulin-resistant state furtherfacilitates insulin secretion from pancreatic 120573-cells whichprobably enhances lipogenesis and results in a vicious cycle[113 261] The coexistence of the hepatic insulin resistanceand sensitivity at the gene expression level has been observedin rodent obese and diabetic models [215 258] Howeverthe mechanism of this coexistence of insulin sensitivity andresistance has not been revealed [261]

Recently the SREBP cleavage-activating protein gene(Scap) an escort protein necessary for generating nuclearforms of SREBPs has been knocked out in insulin-resistantobob mice [262] Deficiency of hepatic Scap reverses liverlipogenesis and steatosis in obobmice However the plasmalevels of glucose and insulin and the hepatic expression levelsof Pck1 andG6pcwere not different between the control obobmice and the obob mice with liver-specific Scap knockout[262] It seems that the suppression of hepatic FA synthesis

12 ISRN Hepatology

is not sufficient to correct insulin resistance Whether otherfactors play a role in the hepatic insulin resistance is still anopen question

The clinical use of RA-based medicine such asisotretinoin (13-cis RA) caused elevation of plasma TGlevels in human subjects [195ndash197] This increase in plasmaTG levels is also observed in rats [201ndash203] From our VAstatus studies we have shown that VA status affected theobesity development in ZF rats and reduced plasma insulinand TG levels in ZL and ZF rats suggesting improvement ofinsulin sensitivity [116] The hepatic expression of Srebp-1cwas reduced in VA-deficient animals [116] RA synergizeswith insulin to induce the expression of Srebp-1c in primaryrat hepatocytes [227] On the other hand RA treatmentinduces Pck1 expression and attenuates insulin-mediatedsuppression of its expression in primary rat hepatocytes [172]All of these observations demonstrate that RA attenuatesinsulin action (insulin-suppressed Pck1 expression) andstill promotes insulin action (insulin-induced Srebp-1cexpression) in the same primary hepatocytes

44 Possible Mechanism by Which RA Production Causes theDevelopment of the Vicious Cycle in Hepatocytes Could RAor other metabolites from VA catabolism be a factor thatcontributes to the hepatic insulin resistance and the viciouscycleUsing the regulation ofPck1 and Srebp-1c as themodel Ihave come upwith the following scheme to show that retinoidmetabolism could be a factor that causes the vicious cycle inthe liver As shown in Figure 3(a) in insulin-sensitive hepa-tocytes RA derived from retinal coordinates with insulin toregulate the expression of Srebp-1c and Pck1 The SREBP-1cprotein is processed to mature form a step that can be facili-tated by insulin [263] The mature form of SREBP-1c entersinto the nucleus and induces the mRNA levels of Raldh1and Fas which are respectively transcribed into RALDH1and FAS RALDH1 catalyzes the conversion of retinal to RAFAS catalyzes the synthesis of palmitate which is esterifiedinto TGs or elongated to longer FAs The Pck1 mRNA isused to translate into PEPCK-C protein which contributesto glucogenogenesis In the insulin-resistant hepatocytes asshown in Figure 3(b) the elevation of Raldh1 expressiondue to leptin deficiency [45] or induction of SREBP-1c byhigh-cholesterol feeding [232] induces the production of RAThe elevated RA levels will stimulate the transcription ofSrebp-1c and Pck1 This leads to more production of SREBP-1c and its mature form in the presence of higher insulinlevels in the insulin-resistant state The induction of SREBP-1c further enhances the transcription of Raldh1 and Fas andtheir corresponding proteins for the production of moreRAs and FAs respectively The RA production and SREBP-1c expression form a feed-forward cycle which causes moreTG and RA production in the insulin-resistant liver At thesame time more of the PEPCK-C protein is generated dueto the elevated Pck1 transcription by RA stimulation whichis not responsive to insulin inhibition as we have shown in[172] This leads to elevated gluconeogenesis in the insulin-resistant liver Eventually the phenotypes appear as if insulin

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1cRetinal

RALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(a) Insulin-sensitive hepatocytes

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1c

RetinalRALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(b) Insulin-resistant hepatocytes

Figure 3 The effects of RA on the insulin-regulated Srebp-1cand Pck1 expression levels the protein levels of SREBP-1c theexpression levels of Raldh1 and Fas and the fatty acid synthesisand gluconeogenesis in insulin-sensitive (a) and insulin-resistant (b)hepatocytes Please see the text in this paper for description Uparrows next to the text indicate induction The intensified weight ofthe lines indicates the induction of that part of the pathway

no longer suppresses gluconeogenesis while it still stimulatesFA synthesis in the insulin-resistant state

5 Perspectives and Future Directions

I have proposed a mechanism by which VA metabolismcontributes to the development of hepatic insulin resistanceIt explains some observations reported in the previous studiesof rodent obese and diabetic models [215 258] However itleavesmore open questionsThefirst one iswhat the initiationfactor is So far the elevated expression of Raldh1 mRNA inthe liver has been observed in ZF rats [45] and mice fed ahigh-cholesterol diet [232] These two conditions cause a lotof physiological changes such as overfeeding in ZF rats andchange of cholesterol biosynthesis in response to the feedingof high-cholesterol diet Knocking down Raldh1 specificallyin hepatocytes is needed to answer these questions The

ISRN Hepatology 13

second question is whether RA synthesis in hepatocytesis a regulated process in response to dietary or hormonalstimulations If Raldh1 is a downstream gene of SREBP-1cit should be regulated when the SREBP-1c level changes Asthe expression of Srebp-1c responds to insulin stimulation andoxysterols the regulation of Raldh1 expression in the livershould be studied The third question is why it is RALDH1but not other RALDHs Specific inhibitors of RALDHsmay be needed to answer this question Last question iswhether we can attenuate insulin resistance by suppressingthe RALDH1 activity in the liver It has been shown thatRaldh1minusminus mice are still insulin sensitive when they are onan HFD [26] This has been attributed to the effects on theadipogenesis However the liver of those knockout mice hasreduced lipid synthesis [231] Further studies are warrantedto answer all of these questions Hopefully it can become anintervention point for the treatment of insulin resistance andmetabolic diseases

Acknowledgments

This work was financially supported by a research grantfrom Allen Foundation Inc (to Guoxun Chen) a start-up fund from the University of Tennessee at Knoxville (toGuoxun Chen) and a Scientist Development Grant fromthe AmericanHeart Association (09SDG2140003 to GuoxunChen) The author thanks his colleague Dr Lauren Gellar forreading through this paper and offering her edits

References

[1] F G Hopkins ldquoFeeding experiments illustrating the impor-tance of accessory factors in normal dietariesrdquo The Journal ofPhysiology vol 44 no 5-6 pp 425ndash460 1912

[2] K J Carpenter ldquoA short history of nutritional science part 3(1912ndash1944)rdquo Journal of Nutrition vol 133 no 10 pp 3023ndash30322003

[3] E V McCollum and M Davis ldquoThe necessity of certain lipinsin the diet during growthrdquo Journal of Biological Chemistry vol15 no 1 pp 167ndash175 1913

[4] T B Osborne and L B Mendel ldquoFeeding experiments with fat-free food mixturesrdquo Journal of Biological Chemistry vol 12 no1 pp 81ndash89 1912

[5] R D Semba ldquoOn the lsquoDiscoveryrsquo of Vitamin Ardquo Annals ofNutrition and Metabolism vol 61 no 3 pp 192ndash198 2012

[6] R Blomhoff and H K Blomhoff ldquoOverview of retinoidmetabolism and functionrdquo Journal of Neurobiology vol 66 no7 pp 606ndash630 2006

[7] A Sommer ldquoVitamin A deficiency and clinical disease anhistorical overviewrdquo Journal of Nutrition vol 138 no 10 pp1835ndash1839 2008

[8] K J Rothman L L Moore M R Singer U-S Nguyen SMannino and A Milunsky ldquoTeratogenicity of high vitamin Aintakerdquo The New England Journal of Medicine vol 333 no 21pp 1369ndash1373 1995

[9] S Bershad A Rubinstein and J R Paterniti Jr ldquoChanges inplasma lipids and lipoproteins during isotretinoin therapy foracnerdquoThe New England Journal of Medicine vol 313 no 16 pp981ndash985 1985

[10] N Rodondi R Darioli A-A Ramelet et al ldquoHigh risk forhyperlipidemia and the metabolic syndrome after an episodeof hypertriglyceridemia during 13-cis retinoic acid therapy foracne a pharmacogenetic studyrdquo Annals of Internal Medicinevol 136 no 8 pp 582ndash589 2002

[11] H-U Klor A Weizel M Augustin et al ldquoThe impact oforal vitamin A derivatives on lipid metabolism what recom-mendations can be derived for dealing with this issue in thedaily dermatological practicerdquo Journal of the German Societyof Dermatology vol 9 no 8 pp 600ndash607 2011

[12] R M Russell ldquoThe vitamin A spectrum from deficiency totoxicityrdquoThe American Journal of Clinical Nutrition vol 71 no4 pp 878ndash884 2000

[13] A C Ross B Caballero R J Cousins K L Tucker and T RZiegler Modern Nutrition in Health and Diseases 11th edition2012

[14] E H Harrison ldquoMechanisms of digestion and absorption ofdietary vitamin Ardquo Annual Review of Nutrition vol 25 no 1pp 87ndash103 2005

[15] M R Lakshman ldquoAlpha and omega of carotenoid cleavagerdquoJournal of Nutrition vol 134 no 1 pp 241ndash245 2004

[16] I Potrykus ldquoNutritionally enhanced rice to combat malnutri-tion disorders of the poorrdquo Nutrition Reviews vol 61 no 6 ppS101ndashS104 2003

[17] A Wyss ldquoCarotene oxygenases a new family of double bondcleavage enzymesrdquo Journal of Nutrition vol 134 no 1 pp 246ndash250 2004

[18] R Kawaguchi J Yu J Honda et al ldquoA membrane receptor forretinol binding protein mediates cellular uptake of vitamin ArdquoScience vol 315 no 5813 pp 820ndash825 2007

[19] P Alapatt F Guo S M Komanetsky et al ldquoLiver retinoltransporter and receptor for serum retinol-binding protein(RBP4)rdquo Journal of Biological Chemistry vol 288 no 2 pp1250ndash1265 2013

[20] A R Moise N Noy K Palczewski and W S Blaner ldquoDeliveryof retinoid-based therapies to target tissuesrdquo Biochemistry vol46 no 15 pp 4449ndash4458 2007

[21] G Duester ldquoFamilies of retinoid dehydrogenases regulatingvitamin A function Production of visual pigment and retinoicacidrdquo European Journal of Biochemistry vol 267 no 14 pp4315ndash4324 2000

[22] M Theodosiou V Laudet and M Schubert ldquoFrom carrotto clinic an overview of the retinoic acid signaling pathwayrdquoCellular andMolecular Life Sciences vol 67 no 9 pp 1423ndash14452010

[23] J L Napoli ldquoInteractions of retinoid binding proteins andenzymes in retinoidmetabolismrdquoBiochimica et BiophysicaActavol 1440 no 2-3 pp 139ndash162 1999

[24] X Chai M H E M Boerman Y Zhai and J L NapolildquoCloning of a cDNA for liver microsomal retinol dehydro-genase A tissue-specific short-chain alcohol dehydrogenaserdquoJournal of Biological Chemistry vol 270 no 8 pp 3900ndash39041995

[25] B X Wu G Moiseyev Y Chen B Rohrer R K Crouch andJ-XMa ldquoIdentification of RDH10 an all-trans retinol dehydro-genase in retinal Muller cellsrdquo Investigative Ophthalmology andVisual Science vol 45 no 11 pp 3857ndash3862 2004

[26] O Ziouzenkova G Orasanu M Sharlach et al ldquoRetinalde-hyde represses adipogenesis and diet-induced obesityrdquo NatureMedicine vol 13 no 6 pp 695ndash702 2007

14 ISRN Hepatology

[27] J L Napoli ldquoPhysiological insights into all-trans-retinoic acidbiosynthesisrdquo Biochimica et Biophysica Acta vol 1821 no 1 pp152ndash167 2012

[28] G Wolf ldquoTissue-specific increases in endogenous all-transretinoic acid possible contributing factor in ethanol toxicityrdquoNutrition Reviews vol 68 no 11 pp 689ndash692 2010

[29] P V Bhat J Labrecque JM Boutin A Lacroix andA YoshidaldquoCloning of a cDNA encoding rat aldehyde dehydrogenase withhigh activity for retinal oxidationrdquoGene vol 166 no 2 pp 303ndash306 1995

[30] M Lin M Zhang M Abraham S M Smith and J LNapoli ldquoMouse retinal dehydrogenase 4 (RALDH4) molecularcloning cellular expression and activity in 9-cis-retinoic acidbiosynthesis in intact cellsrdquo Journal of Biological Chemistry vol278 no 11 pp 9856ndash9861 2003

[31] F A Mic A Molotkov X Fan A E Cuenca and GDuester ldquoRALDH3 a retinaldehyde dehydrogenase that gener-ates retinoic acid is expressed in the ventral retina otic vesicleand olfactory pit during mouse developmentrdquo Mechanisms ofDevelopment vol 97 no 1-2 pp 227ndash230 2000

[32] X Wang P Penzes and J L Napoli ldquoCloning of a cDNAencoding an aldehyde dehydrogenase and its expression inEscherichia coli recognition of retinal as substraterdquo Journal ofBiological Chemistry vol 271 no 27 pp 16288ndash16293 1996

[33] A Molotkov and G Duester ldquoGenetic evidence that retinalde-hyde dehydrogenase Raldh1 (Aldh1a1) functions downstreamof alcohol dehydrogenase Adh1 in metabolism of retinol toretinoic acidrdquo Journal of Biological Chemistry vol 278 no 38pp 36085ndash36090 2003

[34] G Elizondo J Corchero E Sterneck and F J GonzalezldquoFeedback inhibition of the retinaldehyde dehydrogenase geneALDH1 by retinoic acid through retinoic acid receptor 120572and CCAATenhancer-binding protein 120573rdquo Journal of BiologicalChemistry vol 275 no 50 pp 39747ndash39753 2000

[35] G Elizondo I M Medina-Dıaz R Cruz F J Gonzalez and LVega ldquoRetinoic acid modulates retinaldehyde dehydrogenase 1gene expression through the induction of GADD153-CEBP120573interactionrdquo Biochemical Pharmacology vol 77 no 2 pp 248ndash257 2009

[36] K Fujiwara M Kikuchi K Horiguchi et al ldquoEstrogen receptoralpha regulates retinaldehyde dehydrogenase 1 expression in ratanterior pituitary cellsrdquo Endocrine Journal vol 56 no 8 pp963ndash973 2009

[37] K Fujiwara F Maekawa M Kikuchi S Takigami T Yadaand T Yashiro ldquoExpression of retinaldehyde dehydrogenase(RALDH)2 and RALDH3 but not RALDH1 in the developinganterior pituitary glands of ratsrdquo Cell and Tissue Research vol328 no 1 pp 129ndash135 2007

[38] GWolf ldquoThe enzymatic cleavage of 120573-carotene still controver-sialrdquo Nutrition Reviews vol 53 no 5 pp 134ndash137 1995

[39] S Abu-Abed P Dolle D Metzger B Beckett P Chambonand M Petkovich ldquoThe retinoic acid-metabolizing enzymeCYP26A1 is essential for normal hindbrain patterning verte-bral identity and development of posterior structuresrdquo Genesand Development vol 15 no 2 pp 226ndash240 2001

[40] M A Leo S Iida and C S Lieber ldquoRetinoic acid metabolismby a system reconstituted with cytochrome P-450rdquo Archives ofBiochemistry and Biophysics vol 234 no 1 pp 305ndash312 1984

[41] MA Leo JM Lasker J L Raucy C-I KimM Black andC SLieber ldquoMetabolism of retinol and retinoic acid by human livercytochrome P450IIC8rdquoArchives of Biochemistry and Biophysicsvol 269 no 1 pp 305ndash312 1989

[42] R Quere A Baudet B Cassinat et al ldquoPharmacogenomicanalysis of acute promyelocytic leukemia cells highlightsCYP26cytochrome metabolism in differential all-trans retinoic acidsensitivityrdquo Blood vol 109 no 10 pp 4450ndash4460 2007

[43] J AWhite B Beckett-Jones Y-D Guo et al ldquocDNA cloning ofhuman retinoic acid-metabolizing enzyme (hP450RAI) identi-fies a novel family of cytochromes p450 (CYP26)rdquo Journal ofBiological Chemistry vol 272 no 30 pp 18538ndash18541 1997

[44] Y Zhang R Zolfaghari Reza and A C Ross ldquoMultiple retinoicacid response elements cooperate to enhance the inducibility ofCYP26A1 gene expression in liverrdquo Gene vol 464 no 1-2 pp32ndash43 2010

[45] Y Li Y Zhang R Li et al ldquoThe hepatic raldh1 expression iselevated in Zucker fatty rats and its over-expression introducedthe retinal-induced Srebp-1c expression in INS-1 cellsrdquo PLoSONE vol 7 no 9 Article ID e45210 2012

[46] R M Evans ldquoThe nuclear receptor superfamily a Rosetta stonefor physiologyrdquo Molecular Endocrinology vol 19 no 6 pp1429ndash1438 2005

[47] P Chambon ldquoA decade of molecular biology of retinoic acidreceptorsrdquo FASEB Journal vol 10 no 9 pp 940ndash954 1996

[48] D J Mangelsdorf and RM Evans ldquoThe RXR heterodimers andorphan receptorsrdquo Cell vol 83 no 6 pp 841ndash850 1995

[49] J E Balmer and R Blomhoff ldquoA robust characterization ofretinoic acid response elements based on a comparison of sitesin three speciesrdquo Journal of Steroid Biochemistry and MolecularBiology vol 96 no 5 pp 347ndash354 2005

[50] R Kurokawa J DiRenzo M Boehm et al ldquoRegulation ofretinoid signalling by receptor polarity and allosteric control ofligand bindingrdquo Nature vol 371 no 6497 pp 528ndash531 1994

[51] A Cvekl and W-L Wang ldquoRetinoic acid signaling in mam-malian eye developmentrdquo Experimental Eye Research vol 89no 3 pp 280ndash291 2009

[52] V Dupe M Davenne J Brocard et al ldquoIn vivo functional anal-ysis of the Hoxa-1 31015840 retinoic acid response element (31015840RARE)rdquoDevelopment vol 124 no 2 pp 399ndash410 1997

[53] A C Ross ldquoRetinoid production and catabolism role of dietin regulating retinol esterification and retinoic acid oxidationrdquoJournal of Nutrition vol 133 no 1 pp 291ndash296 2003

[54] T Moore and P D Holmes ldquoThe production of experimentalvitamin A deficiency in rats andmicerdquo Laboratory Animals vol5 no 2 pp 239ndash250 1971

[55] A C Ross and E H Harrison ldquoVitamin A and carotenoidsrdquoin Handbook of Vitamins D E McCormick R R Rucker J WSuttie et al Eds CRC Press Boca Raton Fla USA 4th edition2006

[56] A Chawta J J Repa R M Evans and D J MangelsdorfldquoNuclear receptors and lipid physiology opening the x-filesrdquoScience vol 294 no 5548 pp 1866ndash1870 2001

[57] C K Glass and M G Rosenfeld ldquoThe coregulator exchangein transcriptional functions of nuclear receptorsrdquo Genes andDevelopment vol 14 no 2 pp 121ndash141 2000

[58] A L Bookout Y Jeong M Downes R T Yu R M EvansandD JMangelsdorf ldquoAnatomical profiling of nuclear receptorexpression reveals a hierarchical transcriptional networkrdquo Cellvol 126 no 4 pp 789ndash799 2006

[59] B Mascrez M Mark W Krezel et al ldquoDifferential contribu-tions of AF-1 andAF-2 activities to the developmental functionsof RXR120572rdquo Development vol 128 no 11 pp 2049ndash2062 2001

[60] D Li T Li F Wang H Tian and H H Samuels ldquoFunctionalevidence for retinoid X receptor (RXR) as a nonsilent partner

ISRN Hepatology 15

in the thyroid hormone receptorRXR heterodimerrdquoMolecularand Cellular Biology vol 22 no 16 pp 5782ndash5792 2002

[61] F M Sladek W Zhong E Lai and J E Darnell Jr ldquoLiver-enriched transcription factor HNF-4 is a novel member ofthe steroid hormone receptor superfamilyrdquo Genes and Develop-ment vol 4 no 12 pp 2353ndash2365 1990

[62] K Yamagata H Furuta N Oda et al ldquoMutations in thehepatocyte nuclear factor-4120572 gene inmaturity-onset diabetes ofthe young (MODY1)rdquo Nature vol 384 no 6608 pp 458ndash4601996

[63] M Stoffel and S ADuncan ldquoThematurity-onset diabetes of theyoung (MODY1) transcription factor HNF4120572 regulates expres-sion of genes required for glucose transport and metabolismrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 24 pp 13209ndash13214 1997

[64] M Lehto P-O Bitzen B Isomaa et al ldquoMutation in the HNF-4120572 gene affects insulin secretion and triglyceride metabolismrdquoDiabetes vol 48 no 2 pp 423ndash425 1999

[65] G P Hayhurst Y-H Lee G Lambert J M Ward and F JGonzalez ldquoHepatocyte nuclear factor 4120572 (Nuclear receptor 2A1)is essential formaintenance of hepatic gene expression and lipidhomeostasisrdquo Molecular and Cellular Biology vol 21 no 4 pp1393ndash1403 2001

[66] U Roth K Jungermann and T Kietzmann ldquoActivation ofglucokinase gene expression by hepatic nuclear factor 4120572 inprimary hepatocytesrdquo Biochemical Journal vol 365 no 1 pp223ndash228 2002

[67] S Mandard R Stienstra P Escher et al ldquoGlycogen synthase2 is a novel target gene of peroxisome proliferator-activatedreceptorsrdquo Cellular and Molecular Life Sciences vol 64 no 9pp 1145ndash1157 2007

[68] F Rajas A Gautier I Bady S Montano and G MithieuxldquoPolyunsaturated fatty acyl coenzyme a suppress the glucose-6-phosphatase promoter activity bymodulating the DNA bindingof hepatocyte nuclear factor 4120572rdquo Journal of Biological Chemistryvol 277 no 18 pp 15736ndash15744 2002

[69] B Viollet A Kahn and M Raymondjean ldquoProtein kinase A-dependent phosphorylation modulates DNA-binding activityof hepatocyte nuclear factor 4rdquoMolecular and Cellular Biologyvol 17 no 8 pp 4208ndash4219 1997

[70] L Palanker J M Tennessen G Lam and C S Thum-mel ldquoDrosophila HNF4 regulates lipid mobilization and 120573-oxidationrdquo Cell Metabolism vol 9 no 3 pp 228ndash239 2009

[71] A Miura K Yamagata M Kakei et al ldquoHepatocyte nuclearfactor-4120572 is essential for glucose-stimulated insulin secretion bypancreatic 120573-cellsrdquo Journal of Biological Chemistry vol 281 no8 pp 5246ndash5257 2006

[72] R Bartoov-Shifman R Hertz H Wang C B Wollheim JBar-Tana and M D Walker ldquoActivation of the insulin genepromoter through a direct effect of hepatocyte nuclear factor4120572rdquo Journal of Biological Chemistry vol 277 no 29 pp 25914ndash25919 2002

[73] H Wang P Maechler P A Antinozzi K A Hagenfeldt andC B Wollheim ldquoHepatocyte nuclear factor 4120572 regulates theexpression of pancreatic 120573-cell genes implicated in glucosemetabolism and nutrient-induced insulin secretionrdquo Journal ofBiological Chemistry vol 275 no 46 pp 35953ndash35959 2000

[74] K Reue T Leff and J L Breslow ldquoHuman apolipoproteinCIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factorsrdquo Journal ofBiological Chemistry vol 263 no 14 pp 6857ndash6864 1988

[75] T Leff K Reue A Melian H Culver and J L BreslowldquoA regulatory element in the apoCIII promoter that directshepatic specific transcription binds to proteins in expressingand nonexpressing cell typesrdquo Journal of Biological Chemistryvol 264 no 27 pp 16132ndash16137 1989

[76] S N Lavrentiadou M Hadzopoulou-Cladaras D Kardassisand V I Zannis ldquoBinding specificity and modulation of thehuman apocIII promoter activity by heterodimers of ligand-dependent nuclear receptorsrdquo Biochemistry vol 38 no 3 pp964ndash975 1999

[77] T R Magee Y Cai M E El-Houseini J Locker and Y-JY Wan ldquoRetinoic acid mediates down-regulation of the 120572-fetoprotein gene through decreased expression of hepatocytenuclear factorsrdquo Journal of Biological Chemistry vol 273 no 45pp 30024ndash30032 1998

[78] A Qian Y Cai T R Magee and Y J Y Wan ldquoIdentificationof retinoic acid-responsive elements on the HNF1alpha andHNF4alpha genesrdquo Biochemical and Biophysical Research Com-munications vol 276 no 3 pp 837ndash842 2000

[79] H Nakshatri and P Chambon ldquoThe directly repeatedRG(GT)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites forRAR RXR HNF-4 and ARP-1 homo- and heterodimersrdquoJournal of Biological Chemistry vol 269 no 2 pp 890ndash9021994

[80] T Makita G Hernandez-Hoyos T H-P Chen H Wu E VRothenberg and H M Sucov ldquoA developmental transition indefinitive erythropoiesis erythropoietin expression is sequen-tially regulated by retinoic acid receptors andHNF4rdquoGenes andDevelopment vol 15 no 7 pp 889ndash901 2001

[81] T I Kambe J Tada-Kambe Y Kuge Y Yamaguchi-Iwai MNagao and R Sasaki ldquoRetinoic acid stimulates erythropoietingene transcription in embryonal carcinoma cells through thedirect repeat of a steroidthyroid hormone receptor responseelement half-site in the hypoxia-response enhancerrdquo Blood vol96 no 9 pp 3265ndash3271 2000

[82] F-J Lin J Qin K Tang S Y Tsai and M-J Tsai ldquoCoup drsquoEtatan orphan takes controlrdquo Endocrine Reviews vol 32 no 3 pp404ndash421 2011

[83] L-H Wang S Y Tsai R G Cook W G Beattie M-J Tsaiand BW OrsquoMalley ldquoCOUP transcription factor is a member ofthe steroid receptor superfamilyrdquoNature vol 340 no 6229 pp163ndash166 1989

[84] X Leng A J Cooney S Y Tsai and M-J Tsai ldquoMolecularmechanisms of COUP-TF-mediated transcriptional repressionevidence for transrepression and active repressionrdquo Molecularand Cellular Biology vol 16 no 5 pp 2332ndash2340 1996

[85] L Li X Xie J Qin et al ldquoThe nuclear orphan receptorCOUP-TFII plays an essential role in adipogenesis glucosehomeostasis and energy metabolismrdquo Cell Metabolism vol 9no 1 pp 77ndash87 2009

[86] F A Pereira Q Yuhong G Zhou M-J Tsai and S YTsai ldquoThe orphan nuclear receptor COUP-TFII is required forangiogenesis and heart developmentrdquo Genes and Developmentvol 13 no 8 pp 1037ndash1049 1999

[87] N Takamoto I Kurihara K Lee F J DeMayo M-J Tsai andS Y Tsai ldquoHaploinsufficiency of chicken ovalbumin upstreampromoter transcription factor II in female reproductionrdquoMolec-ular Endocrinology vol 19 no 9 pp 2299ndash2308 2005

[88] P Zhang M Bennoun C Gogard et al ldquoExpression of COUP-TFII in metabolic tissues during developmentrdquo Mechanisms ofDevelopment vol 119 no 1 pp 109ndash114 2002

16 ISRN Hepatology

[89] Z Xu S Yu C-H Hsu J Eguchi and E D Rosen ldquoTheorphan nuclear receptor chicken ovalbumin upstream pro-moter-transcription factor II is a critical regulator of adipogene-sisrdquoProceedings of theNationalAcademy of Sciences of theUnitedStates of America vol 105 no 7 pp 2421ndash2426 2008

[90] P Bardoux P Zhang D Flamez et al ldquoEssential role of chickenovalbumin upstreampromoter-transcription factor II in insulinsecretion and insulin sensitivity revealed by conditional geneknockoutrdquo Diabetes vol 54 no 5 pp 1357ndash1363 2005

[91] G Achatz B Holzl R Speckmayer C Hauser F Sandhoferand B Paulweber ldquoFunctional domains of the human orphanreceptor ARP-1COUP-TFII involved in active repression andtransrepressionrdquo Molecular and Cellular Biology vol 17 no 9pp 4914ndash4932 1997

[92] S A Kliewer K Umesono R A Heyman D J MangelsdorfJ A Dyck and R M Evans ldquoRetinoid X receptor-COUP-TFinteractionsmodulate retinoic acid signalingrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol89 no 4 pp 1448ndash1452 1992

[93] A J Cooney S Y Tsai BW OrsquoMalley andM-J Tsai ldquoChickenovalbumin upstreampromoter transcription factor (COUP-TF)dimers bind to different GGTCA response elements allowingCOUP-TF to repress hormonal induction of the vitamin D3thyroid hormone and retinoic acid receptorsrdquo Molecular andCellular Biology vol 12 no 9 pp 4153ndash4163 1992

[94] SW Kruse K Suino-Powell X E Zhou et al ldquoIdentification ofCOUP-TFII orphannuclear receptor as a retinoic acid-activatedreceptorrdquo PLoS Biology vol 6 no 9 Article ID e227 2008

[95] J P Berger T E Akiyama and P T Meinke ldquoPPARs thera-peutic targets for metabolic diseaserdquo Trends in PharmacologicalSciences vol 26 no 5 pp 244ndash251 2005

[96] JM Peters andF J Gonzalez ldquoSorting out the functional role(s)of peroxisome proliferator-activated receptor-120573120575 (PPAR120573120575)in cell proliferation and cancerrdquo Biochimica et Biophysica Actavol 1796 no 2 pp 230ndash241 2009

[97] A Tenenbaum and E Fisman ldquoBalanced pan-PPAR activatorbezafibrate in combination with statin comprehensive lipidscontrol and diabetes preventionrdquo Cardiovascular Diabetologyvol 11 no 1 article 140 2012

[98] O Braissant F Foufelle C Scotto M Dauca and W WahlildquoDifferential expression of peroxisome proliferator-activatedreceptors (PPARs) tissue distribution of PPAR-120572 -120573 and -120574 inthe adult ratrdquo Endocrinology vol 137 no 1 pp 354ndash366 1996

[99] H Higashiyama A N Billin Y Okamoto M Kinoshita andS Asano ldquoExpression profiling of Peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues usingtissue microarrayrdquo Histochemistry and Cell Biology vol 127 no5 pp 485ndash494 2007

[100] P S Jones R Savory P Barratt et al ldquoChromosomal local-isation inducibility tissue-specific expression and strain dif-ferences in three murine peroxisome-proliferator-activated-receptor genesrdquo European Journal of Biochemistry vol 233 no1 pp 219ndash226 1995

[101] S A Kliewer B M Forman B Blumberg et al ldquoDifferentialexpression and activation of a family of murine peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no15 pp 7355ndash7359 1994

[102] E E Girroir H E Hollingshead P He B Zhu G H Perdewand J M Peters ldquoQuantitative expression patterns of peroxi-some proliferator-activated receptor-120573120575 (PPAR120573120575) protein in

micerdquo Biochemical and Biophysical Research Communicationsvol 371 no 3 pp 456ndash461 2008

[103] P Escher O Braissant S Basu-Modak L Michalik W Wahliand B Desvergne ldquoRat PPARs quantitative analysis in adult rattissues and regulation in fasting and refeedingrdquo Endocrinologyvol 142 no 10 pp 4195ndash4202 2001

[104] D Auboeuf J Rieusset L Fajas et al ldquoTissue distributionand quantification of the expression of mRNAs of peroxi-some proliferator-activated receptors and liver X receptor-120572 inhumans no alteration in adipose tissue of obese and NIDDMpatientsrdquo Diabetes vol 46 no 8 pp 1319ndash1327 1997

[105] N ShawM Elholm andN Noy ldquoRetinoic acid is a high affinityselective ligand for the peroxisome proliferator-activated recep-tor 120573120575rdquo Journal of Biological Chemistry vol 278 no 43 pp41589ndash41592 2003

[106] G Wolf ldquoRetinoic acid as cause of cell proliferation or cellgrowth inhibition depending on activation of one of twodifferent nuclear receptorsrdquoNutrition Reviews vol 66 no 1 pp55ndash59 2008

[107] T T Schug D C Berry N S Shaw S N Travis and N NoyldquoOpposing effects of retinoic acid on cell growth result fromalternate activation of two different nuclear receptorsrdquo Cell vol129 no 4 pp 723ndash733 2007

[108] D C Berry and N Noy ldquoAll-trans-retinoic acid repressesobesity and insulin resistance by activating both peroxisomeproliferation-activated receptor 120573120575 and retinoic acid receptorrdquoMolecular and Cellular Biology vol 29 no 12 pp 3286ndash32962009

[109] D C Berry D DeSantis H Soltanian C M Croniger andN Noy ldquoRetinoic acid upregulates preadipocyte genes to blockadipogenesis and suppress diet-induced obesityrdquo Diabetes vol61 no 5 pp 1112ndash1121 2012

[110] M G Borland C Khozoie P P Albrecht et al ldquoStableover-expression of PPAR120573120575 and PPAR120574 to examine receptorsignaling in human HaCaT keratinocytesrdquo Cellular Signallingvol 23 no 12 pp 2039ndash2050 2011

[111] S E OrsquoSullivan and D A Kendall ldquoCannabinoid activationof peroxisome proliferator-activated receptors potential formodulation of inflammatory diseaserdquo Immunobiology vol 215no 8 pp 611ndash616 2010

[112] Z C Yan D Y Liu L L Zhang et al ldquoExercise reduces adiposetissue via cannabinoid receptor type 1 which is regulated byperoxisome proliferator-activated receptor-120575rdquo Biochemical andBiophysical Research Communications vol 354 no 2 pp 427ndash433 2007

[113] J D McGarry ldquoWhat if Minkowski had been ageusic Analternative angle on diabetesrdquo Science vol 258 no 5083 pp766ndash770 1992

[114] TMoore ldquoVitaminA and carotene the vitaminA reserve of theadult human being in health and diseaserdquo Biochemical Journalvol 31 no 1 pp 155ndash164 1937

[115] GWolfMD Lane and B C Johnson ldquoStudies on the functionof vitamin A in metabolismrdquo Journal of Biological Chemistryvol 225 no 2 pp 995ndash1008 1957

[116] Y Zhang R Li Y Li W Chen S Zhao and G Chen ldquoVitaminA status affects obesity development and hepatic expression ofkey genes for fuel metabolism in Zucker fatty ratsrdquoBiochemistryand Cell Biology vol 90 no 4 pp 548ndash557 2012

[117] M Singh V N Singh and T A Venkitasubramanian ldquoEarlyeffects of feeding excess vitamin A hepatic glycogen bloodlactic acid plasma nefa and glucose tolerance in ratsrdquo LifeSciences vol 7 no 5 pp 239ndash247 1968

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

2 ISRN Hepatology

development of VA deficiency will cover clinical symptomsranging from night blindness to the increase of mortalityin patients with measles [7] On the other hand excessiveintake of VA from dietary sources or supplements has beenconsidered to be teratogenic [8] In addition when patientswith acne are treated with retinoic acid (RA) drugs such asisotretinoin (13-cisRA) a significant portion of them develophypertriglyceridemia an undesired side effect [9 10] Patientswith acute promyelocytic leukaemia (APL) treated with RAgain body weight [11] Moreover excessive 120573-carotene intakefrom supplements can also cause detrimental effects [12] Allof these observations demonstrate the broad spectrumofVArsquosphysiological functions

12 The Sources and Storage of VA Since humans andmammals do not synthesize VA its nutritional need has to besatisfied through dietary intake Dietary sources of VA existin two forms preformed VA (retinol or retinyl esters) andprovitamin A carotenoids [13] Preformed VA is mainly inthe form of retinyl esters (REs) from animal sources In thesmall intestine lumen the released REs from digested animalproducts are enzymatically hydrolyzed into retinol and freefatty acids (FFAs) probably by pancreatic lipases esterasesand intestinal phospholipases before being absorbed intoenterocytes with other lipids [14] Inside the enterocytes aportion of retinol is reesterified to REs by the lecithin-retinolacyltransferase (LRAT) or acyl-CoA retinol-acyltransferase(ARAT) REs are packed into chylomicronswith other dietarylipids for the delivery to the rest parts of the body vialymph circulation A small portion of the retinol is directlytransported via portal circulation [15] REs in the plasma andthe liver mainly contain the fatty acyl moieties of palmitateand stearates regardless of the composition of fatty acid (FA)in the diet When triglyceride (TG) is stripped away fromthe chylomicrons by lipoprotein lipase (LPL) REs are stillassociated with chylomicron remnants which are eventuallytaken into hepatocytes In hepatocytes REs are hydrolyzedinto retinol and FFAs again Retinol can be released intothe blood circulation or catabolized into retinal RA andother metabolites for usage or disposal In addition retinolis reesterified into RE again and stored in stellate cells insidethe liver [6]

Provitamin A molecules are from plant sourcesThey are found in colored fruits and vegetables and arenamed carotenoids such as 120573-carotene 120572-carotene and120573-cryptoxanthin [16] Recently with the developmentof transgenic techniques enzymes for the synthesis of120573-carotene have been genetically engineered into the ricegenome [16] The produced rice containing significantamount of 120573-carotene is called golden rice In theory thisrice can be used to provide provitamin A to populationswith low dietary VA availability Carotenoids are convertedinto retinal and then retinol in enterocytes and hepatocytesThe conversion of provitamin A carotenoids to retinalhas two pathways The central cleavage is mediated by120573120573-carotene-15151015840-dioxygenase The eccentric cleavage ismediated by 120573120573-carotene-91015840101015840-oxygenase The resultingretinal is reduced to form retinol [15 17]

REs stored in hepatic stellate cells can be released intohepatocytes again in case of insufficient amount of dietaryVA or provitamin A intake In hepatocytes retinol binds toretinol-binding proteins (RBPs) to form holo-RBPs whichare released into the blood circulation In plasma the holo-RBPs interact with transthyretin (TTR) which binds tothyroxine (T4)This complex transports both retinol and T4Peripheral tissues express RBP receptors such as STRA6 forthe uptake of retinol from plasma [18] Hepatocytes expressRBP4 receptor-2 (RBPR2) which has been considered to beresponsible for plasma retinol homeostasis [19]

13 VA Metabolism VA homeostasis is regulated by a net-work of enzymes and proteins involved in the transportproduction and catabolism of retinoids [20] VArsquos physi-ological functions are mainly mediated by its metabolitesretinal and RA This is achieved via a series of enzymescatalyzing the conversions [21] Two oxidation steps occurduring the conversion from retinol to retinal (retinaldehyde)and then from retinal to RA [22] Retinol is reversiblyconverted into retinal and retinal is irreversibly convertedinto RA [23] Retinol is reversibly oxidized into retinal bytwo families of enzymes alcohol dehydrogenases (ADHs)and retinol dehydrogenases (RDHs) or short-chain dehydro-genasesreductases (SDRs) Two RDHs (RDH2 and RDH10)play major roles in this step in different tissues [24 25]The produced retinal plays important roles in physiologyFor example vision is mediated by 11-cis retinal conjugatedto rhodopsin in response to photon activation Recentlyretinal has been considered an antagonist for the activation ofperoxisome proliferator-activated receptor 120574 (PPAR120574)Whenthe level of retinaldehyde (retinal) was induced in insulin-resistant obob mice after the deletion of Raldh1 gene theirinsulin sensitivity was improved [26]

Retinal is irreversibly oxidized into RA by retinaldehyde(aldehyde) dehydrogenases (RALDHs orALDHs) [21 27 28]Currently four RALDHs (RALDH1 RALDH2 RALDH3and RALDH4) have been cloned and thought to be respon-sible for all-trans or 9-cis RA production in various tissues[29ndash32] They have been collectedly called retinoid dehy-drogenases [21] RALDH1ndash4 proteins were observed in themouse liver based on immunohistochemistry results and theexpression of RALDH1was found in lipid-engorged cells [30]The expression of Raldh1 (also known as Aldh1a1) mRNAwas detected weakly in the rat liver [29] RALDH1 appearsto be the predominant enzyme for RA biosynthesis [33]and elevated RA is observed to control its biosynthesis bydownregulating RALDH1 through modulation of retinoicacid receptor a (RAR120572) and the CCAATenhancer-bindingprotein 120573 (CEBP120573) [34 35] In rat anterior pituitary cellsestrogen receptor alpha can regulate the expression of Raldh1[36]

The expression of RALDH2 and RALDH3 but notRALDH1 can be detected in the developing anterior pituitaryglands of rats [37] The expression of Raldh4 (also known asAldh8a1) mRNA was expressed at high level in the mouseliver [30] Other potential pathways for the RA formationinclude oxidation of retinal by microsomal cytochrome P450

ISRN Hepatology 3

and direct production of RA by cleavage of 120573-carotenein a process that might not involve retinol or retinal asintermediates [38]

In hepatocytes RA can be further modified by enzymessuch as cytochrome P450 26A1 (CYP26A1) to morehydrophilic products [39ndash44] The expression of Cyp26a1mRNA is rapidly induced by RA treatment and is often usedas an indicator of RA production [45]

Other products derived from retinoid metabolism havebeen reported Retroretinoids are a class of retinol derivativesin which the polyene tail is rigidly attached to the 120573-ionone ring by a double bond with the remaining doublebonds retaining the conjugated system and extending it tothe 3 4 double bond within the ring Another bioactiveretinoid is 3 4-dihydroretinol also known as vitamin A2It is abundant in freshwater fish where it is metabolizedinto 11-cis-dehydroretinol which can serve as a ligand forvisual pigments Oxidized retinol metabolites such as 4-oxo-retinoic acid were reported to be highly active indetermining digit development and activation of retinoic acidreceptor 120573 (RAR120573) Some proteins are modified by covalentretinoylation [13]

14 Potential Transcription Factors That Mediate RA EffectsRAR Retinoid X Receptor (RXR) PPAR120573120575 HepatocyteNuclear Factor 4120572 (HNF4120572) and Chicken OvalbuminUpstream Promoter-Transcription Factors (COUP-TFs)

141 Retinoic Acid-Responsive Element (RARE) It has beengenerally believed that the active metabolite of VA RAregulates gene expression through activation of twomembersof nuclear receptors [46] RARs andRXRs [27 28] RARRXRheterodimer or RXRRXRhomodimer associatedwith RAREin the promoters activates the transcription of RA-responsivegenes upon ligand binding [47 48]

RA regulates gene expression through transcription fac-tors bound to RAREs A typical RARE contains two hex-americ motifs 51015840-(AG)G(GT)TCA-31015840 arranged as palin-dromes direct repeats (DRs) or inverted repeats (IRs) [49]These two motifs are separated by nucleotides The commonDRs with 1 2 or 5 nucleotide spacing are termed DR1 DR2and DR5 elements respectively These different DRs maydetermine the regulatory features of the RA-targeted genesWhen bound to DR2 and DR5 elements the 51015840 half-site isoccupied by RXR and the 31015840 half-site by RAR [47] On theother hand the upstream half-site of a DR1 can be recognizedby a RAR a setting that may recruit repressor complexes tosuppress gene expression When bound to DR1 elements thepolarity of the RARRXR heterodimer is inverted and thecomplex is unresponsive to RA stimulation probably dueto the inability of RAR ligands to induce the dissociationof corepressors [50] RXRs can also bind as homodimersto DR1 elements and respond to 9-cis RA By contrast forDR2DR5 elements a RAR occupies the downstream halvesof these RAREs and the complex functions as transcriptionalactivator Additional arrangement of two or three hexamericmotifs with variable spacing has also been identified [51]RARE can be found even in the 31015840 of a gene [52]

142 RARs and RXRs forMediating RAResponses Themajorfunctions of VA are mediated by its active metabolite RA Itis generally believed that all-trans and 9-cis RAs are majorisoforms that mediate the regulation of gene expression [6]However the most important ligand is probably all-transRA as the detection of 9-cis RA produced in a physiologicalsetting has been challenging [6] The RA homeostases iscontrolled by the expression of the enzymes responsible forits production and disposal [53] It is worth noting that somephysiological functions of retinol such as in vision could notbe replaced by RA treatment [54]

RARs and RXRs are members in the nuclear receptorsuperfamily [6 47 55] Nuclear receptors are transcriptionfactors that mediate a complex array of extracellular signalsinto transcriptional responses in a ligand-dependent manner[46] Other members in this family include transcriptionfactors that bind to a variety of physiological activemoleculessuch as endocrine steroids vitamin D thyroid hormone anda large number of ldquoorphanrdquo receptors whose ligands targetgenes and physiological functions were initially unknown[46 56] Upon binding to the ligands nuclear receptorsundergo conformational changes which allow them to inter-act with transcriptional cofactors and in turn regulate theexpression of their target genes [46 57]

RARs and RXRs are widely expressed in metabolic activetissues [58] There are three isoforms each for RARs (RAR120572-120573 and -120574) that bind and respond to all-trans and 9-cis RAsand for RXRs (RXR120572 -120573 and -120574) which can only bind andrespond to 9-cis RA [55] Functional studies have indicatedthat RXRRAR heterodimers act as the main functional unitstransducing RA signals in development which needs theformation of specific heterodimers such as RXR120572RAR120572RXR120572RAR120573 and RXR120572RAR120574 RARRXR heterodimersand RXRRXR homodimers modulate gene expression bybinding to RAREs located in the regulatory regions of theirtarget genes [6 47 55]

Other than RARs many nuclear receptors form het-erodimers with RXRs for binding to their cognate-responsiveelements such as thyroid hormone receptors (TRs) vita-min D3 receptors (VDRs) and PPARs [46] So far RXRsare considered binding partners for other nuclear receptorpathways The activation states of RXRs differ among theseheterodimers and seem to depend on the nature of theirpartners and the binding elements For example in the caseof RARRXR heterodimer either one can be transcriptionallyactive However the ligand-bound RXR is not active unlessits RAR partner binds to a ligand [59] Either PPARs orRXRs in a PPARRXR heterodimer can bind to their agonistsand activate transcription The presence of both ligandsresults in synergistic activation Liver X receptor (LXR)RXRheterodimer retains 9-cis RA responsiveness indicating thatRXR is active upon ligand binding [46] By contrast theTRRXR and VDRRXR heterodimers are thought to benonpermissive as they are activated by the TR ligand tri-iodothyronine (T3) and VDR ligand 125-dihydroxy-VD3(calcitriol) respectively but not by RXR-specific ligands Itis generally believed that in a nonpermissive heterodimerRXR is incapable of binding to its ligands and thus it isoften referred to as a silent partner However recent data

4 ISRN Hepatology

indicated that RXR was able to bind to ligands and leadto dissociation of corepressors from TR thus modulatingheterodimer activity [60]

143 HNF4120572 for Mediating RA Responses Originally HNF-4120572 (NR2A1 gene Nr2a1) was identified as a transcriptionfactor enriched in liver nuclear extract and was responsiblefor transthyretin gene transcription [61] HNF4120572 is a highlyconserved member of the nuclear receptor superfamilyHNF4120572 binds to DNA as a homodimer and acts as a positivetranscriptional regulator of many hepatic genes Expressionof Nr2a1 gene is driven by two distinct promoters the P1promoter that drives expression of splice variants HNF41205721-6in the liver kidney and intestinecolon and the P2 promoterthat drives expression of splice variants HNF41205727-9 in theintestinecolon stomach and 120573-cells of the pancreas Anonsense mutation (Q268X) in exon 7 of the Nr2a1 genethat caused a deletion of 187 C-terminal amino acids of theHNF4120572 protein was indentified in patients with maturity-onset diabetes of the young type I (MODY1) an autosomaldominant early-onset form of noninsulin-dependent dia-betesmellitus (NIDDM) [62]This shortenedHNF4120572 proteinlacks transcriptional activity and fails to dimerize and bind toDNA [63] Another mutation due to a 2 bp deletion in exon3 of the HNF4120572 gene which results in a truncation of theNr2a1 protein to 122 instead of 465 amino acids causes thecarriers to have significantly lower levels of plasma TG andapolipoprotein CIII (apoCIII) than normal subjects [64]

The roles of HNF4120572 have been studied extensively Liver-specific knockout of HNF4120572 resulted in the reduction ofplasma levels of TG and cholesterol accumulation of hepaticlipid contents and decrease of hepatic expression levels ofapolipoproteins AII AIV CII and CIII [65] Moreover ithas been shown that HNF4120572 can activate the expressionof hepatic glucokinase gene (Gck) after it binds to the Gckpromoter [66]

It seems that there is an interaction of PPAR120572 andHNF4120572signaling pathways In the promoter of mouse glycogensynthase 2 gene (Gys2) there are two putative PPAR responseelements (PPREs) one in the upstream promoter and onein intron 1 [67] The DR1 PPRE in the upstream promoterregion is the response element for HNF4120572 The expressionlevel of Gys2 mRNA in the liver of Nr2a1minusminus mice isdramatically lower than that of the wild-type controls Inaddition the Gys2mRNA level in the liver of Pparaminusminusmiceis also lower than that of the wild-type control mice PPAR120572ligand Wy14643 no longer induces Gys2 mRNA expressionin primary hepatocytes of Pparaminusminus mice In Hep2G cellsPPAR120572 activation significantly reduced HNF4120572-dependenttransactivation of Gys2 promoter demonstrating the interac-tion of their signaling pathways [67]

HNF4120572 although initially believed to be an orphanreceptor activity can be modulated by fatty acyl-coenzyme A(CoA) thioesters [68] and also by protein kinase A-mediatedphosphorylation [69] For drosophila HNF4 (dHNF4) regu-lates lipid mobilization and 120573-oxidation [70] Mutant larvaewith dHnf4 deletionwere unable to efficientlymobilize storedfat for energy during starvation consistent with reduced

expression of genes that control lipid catabolism and 120573-oxidation It seems that FAs released from TGs can activatedHNF4 in fasted drosophila which in turn drives FA oxida-tion for energy production [70] This suggests that HNF4120572may be responsive to dietary signals and important in thecontrol of metabolic status

It has been shown that HNF4120572 is responsible for thefunctions of pancreatic 120573-cells The pancreatic 120573-cell-specificNr2a1minusminus knockout mice have impaired glucose-stimulatedinsulin secretion [71] HNF4120572 activates the insulin geneexpression through indirect and direct mechanisms [72]HNF4120572 also regulates the expression of other pancreatic120573-cell genes involved in glucose metabolism and nutrient-induced insulin secretion including glucose transporter-2and liver-type pyruvate kinase [73]

A relationship between RA signaling pathway andHNF4120572 activation has been indicated in the regulation ofthe hepatic gene expression Multiple sites in the promoterof human apoCIII (APOC3) are responsible for positive andnegative regulation of its transcription in HepG2 cells andthe proximal sequence of a 13-nucleotide element for thepositive regulation of the APOC3 transcription is identicalbetween human and rat genomic sequences [74] It has beenshown that different proteins or forms of the same proteinin the nuclear extract from HepG2 and Hela cells bound tothe same 13-nucleotide sequence element in the promoterof the APOC3 gene [75] The activity of this element is notaffected by its orientation in a reporter construct [75] Theproximal hormone-responsive element B (minus87minus72) bindsstrongly to HNF4 ARP1COUP-TFII EAR2COUP-TFIIIEAR3COUP-TFI and RXR120572RAR120572 heterodimers and lessefficiently to homodimers of RAR120572 and heterodimers ofRXR120572with TR120573 or PPAR120572 [76] InHep3B cells the treatmentof RA caused the reduction ofNr2a1mRNA [77] and HNF4120572protein levels after the RA treatment for 3 days [78]

It was found that RA-mediated downregulation of 120572-fetoprotein gene is dependent on the inhibition of HNF1and HNF4120572 in Hep3B cells [77] Since there is no RARE atthe Nr2a1 gene promoter the mechanism for RA-mediatedinhibition of HNF4120572 remains to be investigated On the otherhandHNF4120572 regulates retinoidmetabolism by activating thetranscription of CRBPII gene [79] Furthermore it has beensuggested that HNF4120572 and RXR120572 compete for occupancyof the same site in erythropoietin gene (Epo) promotersequentially regulating its expression during embryogenesis[80] In the development of mouse embryo the hepaticexpression of erythropoietin is sequentially regulated byRARs and HNF4120572 at days E1025 and E1225 respectively[80] This DR2 RARE is in the 31015840 hypoxia-response enhancerof Epo gene and is responsible for RA-mediated inductionof Epo gene in P19 and F9 embryonal carcinomas but not inHep3B cells [81]

144 COUP-TFII for Mediating RA Responses Chicken oval-bumin upstream promoter-transcription factors (COUP-TFs) are members of a family of evolutionarily con-served orphan nuclear receptor without known physio-logical ligand Currently this family has three members

ISRN Hepatology 5

COUP-TFINR2F1ErbA-related protein-3 (EAR3) COUP-TFIINR2F2apolipoprotein-AI regulatory protein-1 (ARP1)and COUP-TFIIINR2F6 (EAR2) [82] COUP-TFs are con-servative among all species with the ligand-binding domainsof COUP-TFI or -II being identical in vertebrates

The cloning and analysis of COUP-TFII (gene NR2F2)cDNA from Hela cells indicate that it is a member ofnuclear receptor superfamily [83] COUP-TFII seems to berequired earlier in the development processes than COUP-TFI COUP-TFII has been thought to suppress gene expres-sion [84] It has been shown to function in a variety of biolog-ical processes such as development cellular differentiationgrowth and metabolic homeostasis [85] Deletion of Nr2f2in mouse is lethal [82] It has been shown that mice withhomozygous deletion of Nr2f2 die at around E10 probablydue to severe hemorrhage and edema and only one-thirdof the heterozygote mice survive before weaning [86] Nr2f2heterozygous pups have growth retardation in comparisonwith their wild-type controls [87] Adult Nr2f2 heterozygousknockout mice have lower body weight and basal plasmainsulin level but higher insulin sensitivity than that of theirwild-type controls [85] They also exhibit resistance to high-fat diet- (HFD-) induced obesity and improved glucosetolerance [85]

COUP-TFII expression can be detected in a variety ofmetabolic active tissues and organs [88] Since heterozygousmice withNr2f2 deletion have improved glucose homeostasisand increased energy expenditure this indicates that COUP-TFII also plays roles in white adipose tissues developmentand energy metabolism [85] COUP-TFII may suppressadipogenesis via inhibiting the expression of genes foradipocyte differentiation such as the expression of sterolregulatory element-binding protein-1c (SREBP1c) PPAR120574and CCAATenhancer-binding protein 120572 (CEBP120572) [89]COUP-TFII regulates the expression of insulin gene andseveral other genes involved in glucose and lipid metabolismin pancreatic 120573-cells Heterozygous mice with Nr2f2 deletionin pancreatic 120573-cells have impaired glucose sensitivity andabnormal insulin secretion [90]

COUP-TFII regulates gene expression via both protein-protein and protein-DNA interactions [76] For exampleCOUP-TFII binds to hormone response elements (HREs)recognized by other nuclear receptors and in turnmodulatesthe expression of these genes It has been shown that COUP-TFII can bind to a variety of HREs that contain direct orinverted imperfect AGGTCA repeats with various spacesCOUP-TFII can also interact with the common partners orgeneral transcriptional factors to modulate gene expression[84 91] For example the amount of RXR available for theformation of high-affinity DNA-binding complexes of thethyroid hormoneRAR subfamily can be limited COUP-TFIIcan also actively silence basal and activated transcriptionlikely through direct interaction with TFIIB or other generaltranscription factors [84]Therefore COUP-TFII may antag-onize the functions of other hormones and in turn alter thecellular responses to multiple-hormone signaling pathwaysand it can have profound effects on metabolic homeostasis

COUP-TF protein interacts with RXR120572 to form het-erodimer [92] Using RXR120572 cDNA probe COUP-TFs were

identified to bind to RAREs The original COUP-TF-bindingsite in the ovalbumin gene is also a RARE that is repressedby COUP-TF [93] On the other hand RXR120572 and COUP-TFII can bind to the same DR1 element individually or inthe heterodimeric form in an electrophoresis mobility shiftassay (EMSA) Cotransfection of COUP-TFII and RXR120572suppresses RXR-mediated activation of CRBPII promoterwhich contains one RARE [92] COUP-TFs are involved inthe modulation of RAR- and RXR-mediated responses toretinoids during embryogenesis [84] Recently COUP-TFIIhas been identified as a low-affinity RA receptor The ligandbinding of COUP-TFII is in an autorepressed conformationAt high concentrations RA is able to promote COUP-TFIIto recruit coactivators and to activate a COUP-TF reporterconstruct [94] These observations suggest a linkage betweenRA and COUP-TFII signaling pathways

145 PPAR120573120575 forMediating RAResponses PPARs aremem-bers of nuclear receptor superfamily They take part in theregulation of a variety of physiological functions such as celldifferentiation metabolism and immune functions [95] Sofar three PPAR isoforms PPAR120572 PPAR120573120575 and PPAR120574are identified and reported The expression of PPAR120573120575 isubiquitous which can be detected in a lot of cell typesand tissues [96 97] In rats PPAR120573120575 mRNA and proteinsare expressed ubiquitously and often coexpressed with otherPPARs [98] Similar expression profiles are observed inmice [99ndash101] In mice PPAR120573120575 protein can be detectedin a variety of tissues with high expression levels in thesmall intestine skin and liver [102] The expression levels ofPPAR120573120575mRNA and protein in the liver of rats fasted for 12hours are reduced and increased upon refeeding for 45 hours[103]The expression of low levels of human PPAR120573120575mRNAcan be detected in the adipose tissues the skeletal muscle theliver the kidney and the intestines [104]

It has been shown that RA is a high-affinity ligand(nanomolar range) for PPAR120573120575 activation in COS-7 cells[105] RA-mediated activation of PPAR120573120575 plays a role incell proliferation [106] In certain types of cells RA isrespectively delivered to RAR and PPAR120573120575 by cytosolretinoic acid-binding protein II (CRABP-II) and fatty acid-binding protein 5 [107] The activation of these two receptorsby RA has opposite effects on cell growth RA can activatePPAR120573120575 in preadipocytes and mature adipocytes [108 109]RA treatment prevents obesity development in diet-inducedobesity (DIO) via increase of lipolysis [108] and inhibition ofadipocyte differentiation [109]

However when human PPAR120573120575 was stably over-expressed in human keratinocyte cells no change inPPAR120573120575 target gene expression could be observed after thetreatment of RA [110] Many studies have shown that endo-cannabinoids regulate the activity of PPARs via direct andindirect mechanisms [111] The expression of endocannabi-noid receptor type 1 (CB1) is reduced upon overexpressionof PPAR120573120575 suggesting other pathways that PPAR120573120575 isinvolved in [112]

In summary retinol in hepatocytes can be either storedas REs or oxidized into retinal as shown in Figure 1 RA

6 ISRN Hepatology

HepatocyteCell membrane

RE Retinol Retinal RA

Other metabolic pathwaysNuclear

membrane

Cytosol RAOther ligands

RARRXR PPAR120573120575

COUP-TFII UpdownmRNAHNF4120572HNF4120572

RARE

Nucleus

Figure 1 The effects of RA production and other metabolicfactors on the activities of transcription factors associated with aretinoic acid-responsive element (RARE) in the promoter of anRA-targeted gene In primary hepatocytes RA is produced fromretinal derived from retinol Retinol can be esterified into retinylester (RE) or oxidized into retinal The RARE can be occupied byretinoic acid receptor (RAR) retinoid X receptor (RXR) hepatocytenuclear factor 4120572 (HNF4120572) chicken ovalbumin upstreampromoter-transcription factor II (COUP-TFII) and peroxisome proliferator-activated receptor 120573120575 (PPAR120573120575) in the forms of heterodimers orhomodimers These transcription factors receive signals from RAand metabolic pathways and regulate the expression of the RA-responsive gene

is dynamically produced and sent to nucleus where itinteracts with transcription factors associated with RAREin the enhancer regions of the RA-responsive genes Sofar the transcription factors that can be associated with aparticular RARE include RAR RXR COUP-TFII HNF4120572and PPAR120573120575 They form heterodimers or homodimers andbind to RARE to regulate the transcription rate of that geneThe nuclear receptors that occupy the RARE at any givenmoment may be determined by the VA status of the animaland the developmental differentiation and metabolic statesof hepatocytes These transcription factors integrate signalsfrom RA and other metabolic pathways to control the geneexpression positively and negatively Other metabolic signalsin combination with RA may affect the occupancy of thenuclear receptors bound to the RARE and their activationsand may in turn alter the outcomes of the RA-mediatedtranscription responses

2 VArsquos Roles in Glucose Metabolism

As a convenient energy source glucose can be used by all cellsthat are in charge of different physiological functionsGlucoseis metabolized differently in response to hormonal and nutri-tional statuses [113] Hepatocytes utilize and produce glucosedepending on the physiological needs and feeding status ofa subject These processes are regulated by nutritional andhormonal stimuli VA status has been implied to play a role

21 The Effects of VA Status on Hepatic Glycogen ContentsThe roles of VA in glucose metabolism had been suggestedIn 1937 the liver samples of patients who died of diabetesshowed an elevation of VA contents [114] When rats werefed a VA-deficient (VAD) diet to induce VA deficiency theirliver glycogen content was depleted [115] Since VA deficiencyalso caused reduction of food intake in the VAD rats a pair-feeding control group was included The pair-fed rats withequal energy intake as that of VAD rats had higher hepaticglycogen content [115] This depletion of hepatic glycogencontent was attributed to the reduction of glycogenesisfrom trioses rather than directly from glucose [115] Thephenomenon of the depletion of hepatic glycogen contentin the liver of VAD rats has also been observed recently inmy lab [116] On the other hand when rats were fed a dietwith excessive amounts of VA for two days an elevation ofthe hepatic glycogen content in the liver after fasting wasobserved [117] It seems that hepatic VA content is directlycorrelated with the hepatic glycogen content

22 The Effects of Animal VA Statuses and Retinoids onHepatic Gck Expression To initiate the hepatic glucose uti-lization glucose is phosphorylated into glucose 6-phosphateby hexokinases in the first reaction of glycolysis So far fourhexokinase isozymes hexokinase I (A) II (B) III (C) andIV (D) have been identified They have different tissue dis-tributions intracellular locations and kinetic characteristicsMammalian hexokinase IV (D) is also known as glucokinase(GK) (ATP d-hexose 6-phosphotransferase EC 2711) [118ndash121] Mutations of GK have been associated with MODY[122] GK has two unique features that differentiate it fromother hexokinase family members It has low affinity forglucose (higher Km) and it is insensitive to allosteric inhi-bition mediated by physiological concentrations of glucose6-phosphate whereas other hexokinases are sensitive to it[118 121 123 124] In addition to glucose other substrates ofGK include fructose mannose and 2-deoxyglucose [118]

Generally GK activity is mainly observed in the liverand pancreatic islets The 120573-cells and liver GK isoforms havesimilar kinetic properties [125 126] In the short term theGK activity can be regulated via allosteric interactions andcovalent modifications such as binding to GK regulatoryprotein [127] phosphorylation by protein kinase A [128] andinteractionwith a cytosolic GK-associated phosphatase [129]

The long-term regulation of GK activity is done throughthe transcription of its gene Gck which is differentiallyregulated by an upstream promoter in pancreatic 120573-cells anda downstream promoter in hepatocytes [130 131] Using astrain of transgenic mice containing the cDNA of humangrowth hormone gene driven by an upstream Gck promoterfragmentGck expression has been found in certain neuroen-docrine cells of the pancreas pituitary brain gut thyroidand lungs [132] Activation of the upstream or downstreampromoter leads to the generation of a Gck mRNA with aunique 51015840 sequence derived from exon 1120573 or 1L respectivelySince the translation initiation coden is located in the firstexon the GK proteins encoded by the different transcriptsdiffer in the first 15 amino acids at the amino terminus

ISRN Hepatology 7

[130 131] The mechanisms by which the upstream and thedownstream promoters are selectively activated in differentcells have not been revealedThe temporal and special controlof the promoter selectionmust be determined by signals fromdifferentiation and development processes

The upstream and downstream promoters are activatedbased on the hormonal and nutritional conditions of thesubject For example the hepatic but not the pancreatic 120573-cell Gck expression is reduced while fasting and increasedwhile refeeding [130] In the rat liver insulin and glucagonrespectively induce and inhibit the expression of GckmRNA[133ndash135] A long-standing question in the field is the insulin-responsive element (IRE) responsible for the insulin-inducedhepaticGck expression Using the reporter gene constructs tostudy insulin-induced Gck promoter activation has not beensuccessful For example a reporter gene construct containinga fragment of 55 kb hepatic Gck promoter failed to showany response to insulin treatment in rat primary hepatocytes[136] This suggests that the IRE of the hepatic Gck mightbe in an area not included in this 55 kb promoter fragmentAlternatively the unresponsiveness to insulin of the reportergene constructs in the experimental settings could be due tothe short-lived signal from insulin for Gck transcription aswe have shownpreviously [137] Interestingly the hepatocyte-specific enhancer region that controls the activation of liver-specific promoter has been located in the region from minus1003to minus707 relative to the transcription initiation site in primaryrat hepatocytes By contrast this region acts as a silencer inFTO-2B hepatoma cells and has no effects on insulinomacells [138] Further studies are needed to identify the insulin-responsive element in the hepatic Gck promoter

The direct effects of RA on the expression of Gck mRNAin primary rat hepatocytes have been studied Previouslyothers have shown that all-trans RA induced Gck expressionin primary rat hepatocytes However nonadditive effect ofRA on insulin-induced Gck expression was observed [139140] Recently we have shown that retinoids synergized withinsulin to induce Gck expression in primary rat hepatocytes[137] We have observed that all-trans retinol retinal and RAare able to synergize with insulin to induce Gck expressionprobably via the activation of RARRXR in primary rat hepa-tocytes In addition VA status also controls the expression ofhepatic Gck expression [137] The levels of Gck mRNA [116]and its activity [137] in the liver of VAD rats are lower thanthose of VA-sufficient (VAS) controls In addition a singletreatment of RA increases the hepatic Gck expression in rats[137]

23 The Effects of Animal VA Status and Retinoids onPck1 Gene Expression The plasma glucose homeostasis isachieved through its dietary intake and production fromendogenous noncarbohydrate sources During fasting glu-cose is generated via gluconeogenesis The cytosolic form ofphosphoenolpyruvate carboxykinase (PEPCK-C EC41132)which catalyzes the conversion of oxaloacetate into phos-phoenolpyruvate in the presence of GTP [141] has beenconsidered to be the first rate-limiting enzyme of gluconeoge-nesisThe expression of PEPCK-C gene (Pck1) and its activity

have been detected in the liver kidney adipose tissues andsome other tissues [141ndash143] Other than gluconeogenesisPEPCK-C activity has been considered to be responsible forglyceroneogenesis and cataplerosis [144] Since no allostericregulator of PEPCK-C has been identified its activity isprimarily controlled by the level of Pck1mRNA [141ndash143]

The transcription of hepatic Pck1 is regulated by hor-monal and nutritional stimuli In the liver fasting diabetescarbohydrate-free diets and high-fat diets increase Pck1 geneexpression whereas refeeding insulin treatment and high-carbohydrate diets decrease Pck1 gene expression Glucagonglucocorticoids thyroid hormone and RA induce hepaticPck1 expression while insulin and glucose inhibit it [145]

The transcription regulation of Pck1 has been studiedextensively [142 143] The protein-binding sites at the prox-imal region of rat Pck1 promoter have been determined byDNase I footprinting assays [146 147] Multiple regulatoryelements including distal proximal cyclic AMP-responsiveelement (CRE) [148] have been identified Proteins in ratliver nuclear extracts can interact with the two CREs andsix additional binding sites (P1 to 6) [142] The transcrip-tion factors that bind to these sites include HNF4120572 [149]glucocorticoid receptor [148 150ndash153] RAR [154ndash157] TR[154 158] LXR [159] COUP-TF [149] the Forkhead familyof transcription factors [160] CEBP and cAMP regulatoryelement-binding (CREB) protein [161] and SREBP-1c [162163] Additionally transcription coactivators such as CREB-binding protein (CBP) [164] steroid receptor coactivator 1(SRC1) [165] and peroxisome proliferator-activated receptorgamma coactivator-1-alpha (PGC-1120572) [166] also participatein the regulation of hepatic Pck1 gene expression

Using reporter gene assays and hepatoma cells twoRAREs have been identified in the hepatic Pck1 promoter[154 155 167]WhenPEPCKbovine growth hormone (bGH)transgenic mouse strains are used VA deficiency causes thereduction of the transgenersquos transcription [167]The RARE1 isconsidered to be important for mediating the RA-regulatedPck1 expression in the mouse liver [157] In mice VA statusaffects the association of RNApolymerase II and histone codeof Pck1 promoter [168 169] Later on these RAREs have beenshown to bind toHNF4120572 RXR120572 RAR120572 PPAR120572 and COUP-TFII [170]

In an attempt to study the lipophilic molecules that affectinsulin-regulated gene expression in primary rat hepatocyteswe have obtained lipophilic extract (LE) from the rat liverMyoriginal study has shown that this LE induces Pck1 expressionand attenuates insulin-mediated suppression of Pck1 tran-scription in primary rat hepatocytes [171] Interestingly thesame LE synergizes with insulin to induce Gck expression inthe same cells [137]The activemolecules in the LE are retinoland retinal [137] We have shown that retinol retinal andRA all can affect insulin-suppressed Pck1 expression [172]In rat primary hepatocytes the proximal one of the twoRAREs in the rat Pck1 promoter [154ndash156] is responsiblefor mediating the retinoid effects [172] The expression ofhepatic Pck1mRNA in rats seems to respond to VA deficiencydifferently from that in mice We have shown that the hepaticPck1mRNA level in the Zucker lean (ZL) rats is not reduced

8 ISRN Hepatology

Hepatocyte

Induction

Induction

Induction

1 2

Gck

Pck1

Cell membraneCytosol

RA RA

RARESynergy

Signalcascade Insulin

AttenuationNuclear

membrane NucleusRAREs

Inhibitio

n

Figure 2 RA synergizes with insulin to induce Gck expressionand attenuates insulin-suppressed Pck1 expression RA inducesthe expression levels of Gck and Pck1 via the activation of bothRARRXR (the oval dimmers on the RAREs) in the absenceof insulin Insulin alone stimulates the expression of Gck andsuppresses the expression of Pck1 In the presence of both insulinand RA the expression of Gck is further increased (synergy) Onthe other hand the insulin-mediated suppression of Pck1 expressionis attenuated This is because RA still induces Pck1 expressionvia activation of RAR in the presence of insulin Therefore Pck1transcript level in the RA + insulin group is higher than that in theinsulin group (attenuation)

in VA-deficient state [116] VA deficiency only reduces thehepatic Pck1mRNA in the Zucker fatty (ZF) rats [116]

It is important to note that the respective activities of GKand PEPCK-C are induced in different physiological condi-tions For example insulin induces Gck and suppresses Pck1expression as shown in Figure 2 In primary rat hepatocytesactivation of either RARs or RXRs by RA is sufficient toinduce the expression of both Pck1 [172] and Gck [137] How-ever activation of RAR potentiates (for the insulin-mediatedinduction of Gck expression) and attenuates (for the insulin-mediated suppression of Pck1 expression) insulin actionsat the same time in the same hepatocytes For Gck RA-mediated activation of RARs and RXRs can be potentiated byinsulin [137] which results in the synergy For Pck1 only RA-activated RXRs but not RARs are inhibited by insulin whichresults in the attenuation [172] This causes the production ofmore Pck1 mRNA in the presence of RA than in the absenceof it even in the insulin-suppressed state It indicates that themechanisms of RA-mediated activation of RARs and RXRsprobably depend on the promoter context or the isoformsassociated with the promoters of their downstream genesin the presence of insulin Therefore the roles of retinoidsin hepatic glucose metabolism deserve further investigationespecially the roles of the interactions between retinoidsand insulin signaling pathways in the regulation of genetranscription

24 Role of RBP4 in Insulin Resistance Plasma VA is boundto RBP4 which is mainly produced in the liver [13] TheRbp4 mRNA is also expressed to a certain extent in adipose

tissues and kidney [13] In the plasma retinol-RBP4 complexis associated with transthyretin (TTR) a process to increasethe size of the holo-RBP4-TTR complex to reduce the lossduring renal filtration [173]

Recently the plasma RBP4 has been suggested to playroles in metabolic homeostasis It has been reported thatinsulin-resistant human subjects and animals have higherplasma RBP4 levels than normal ones due to its elevatedproduction from adipose tissues [174] In mice RBP4administration has been shown to reduce insulin sensitivityand increase the expression levels of hepatic gluconeogenicgenes such as Pck1 and the catalytic subunit of glucose 6-phosphatase (G6pc) [175] Additionally reduction of plasmaretinol and RBP levels has been reported in type 1 diabeticpatients [176] and in streptozotocin- (STZ-) induced diabeticrats [177] Rbp4 knockout mice have improved insulin sen-sitivity [175] The treatment fenretinide a synthetic retinoidderivative that disrupts the association of RBP4 and TTRimproves insulin sensitivity in HFD-induced obese mice[175]

When a compound specifically developed to disrupt theRBP4 and TTR interaction was used to treat mice it suc-cessfully disrupted the formation of RBP4-TTR complex andcaused the reduction of plasma RBP4 level [178] Howeverthe reduction of plasma RBP4 level did not result in animprovement of insulin sensitivity [178] In addition theimprovement of insulin sensitivity in Rbp4 knockout micecould not be observed in this study [178] Therefore the ele-vation of insulin sensitivity in mice treated with fenretinideis probably due to a mechanism other than the disruption ofRBP-TTR complex and reduction of plasma RBP4 levels

3 Roles of VA in FA and TG Metabolism

FAs are needed for many aspects of cellular functions fromsignal transduction to energy production The continuoussurvival of a given cell depends on the constant energysupplies from the environment or storage sources Thestorage of FA in the form of TG ensures the constant energysupply in a cell or organism for a prolonged period oftime when environment energy is limited In animals thehomeostasis of FA and TG is dynamically regulated by theliver and the adipose tissues in response to nutritional andhormonal stimuli [179 180] During fasting or starvation FAsare released from adipose depots after lipolysis and oxidizedin the liver and muscle for energy production [181] Afterrefeeding dietary and newly synthesized FAs are convertedto TGs for the storage in the adipose tissues [182] On theother hand the altered regulation of this system may causeproblems For example the excessive synthesis and storage ofFAs in the form of TGs can cause the development of obesityand other metabolic diseases

31 The Effects of VA Status on the Body Fat and Plasma LipidProfile VA was first recognized as a dietary lipophilic factorwhich was essential to support the normal growth of labanimals [3 4] Subsequently it was observed that along withthe reduction of body mass the VAD rats that had been fed

ISRN Hepatology 9

aVADdiet at weaning (21 days old) formore than 9weeks hadreduction of carcass fat but not cholesterol content [183] Onthe other hand this reduction of body fat was not observedin the rats of the pair-feeding group which were given thesame amount of a VAS diet in weight and calories as theone consumed by the VAD rats [183] These results indicatethat the reduction of food intake alone could not be used toexplain the depletion of body fat in the VAD rats

The VA status also seems to affect the hepatic expressionof apo AI mRNA The expression of hepatic apo AI hasbeen shown to be sensitive to VA status [184] When theLewis strain rats develop VA deficiency the expression levelof hepatic but not intestinal apo AI mRNA is elevated Thisinduction is dropped upon single dosage of RA treatment[184] On the other hand in the intestine and liver of VA-deficient Wistar rats both all-trans RA and 9-cis RA caninduce apo AI mRNA levels [185] The same treatment canonly induce the mRNA level of apo CIII in the intestine butnot in the liver [185] In humans the plasma VA levels arepositively correlated with the elevations of proteins of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiapatients [186]

When male Wistar rats were fed a VAD diet for 3 monthsafter weaning (21 days old) they had lower plasma TGs andcholesterol levels than the control ones fed a VAS diet [187]When the hepatic synthesis of FAs and phospholipids wasanalyzed in the liver slices the incorporations of [14C]cholineinto phosphatidylcholine and [14C]acetate into FAs were alsoreduced in the VAD rats compared with their VAS controls[187] The VAD rats had lower activities and mRNA levels ofacetyl-CoA carboxylase but higher activity and mRNA levelof carnitine palmitoyltransferase-I than VAS rats had [187]These results demonstrate that there is a reduction of hepaticfatty acid synthesis along with an induction of hepatic fattyacid oxidation in the liver of VAD rats

My lab has conducted experiments and shown that VAstatus affects the obesity development in ZF rats and controlsplasma TG levels in ZL and ZF rats [116] ZF rats a ratmodel of obesity development [188] develop obesity dueto a missense mutation in the extracellular domain of allleptin receptor isoforms [189ndash191] They have been used forthe studies of obesity insulin resistance and other aspectsof metabolic diseases [192 193] We have analyzed growthplasma parameters and expression levels of hepatic genes ofmale ZL and ZF rats fed a VAD or a VAS diet at weaning(21 days of age) for 8 weeks Body masses of ZL and ZF ratsfed the VAD diet are lower than those of their correspondingcontrols fed the VAS diet at the end of the feeding periodThe VAD ZL or ZF rats begin to take less food than the VASones after five weeks on the diet The VAD ZL or ZF rats havelower plasma glucose TG insulin and leptin levels than theircorresponding VAS rats have The liver glycogen content netweights of epididymal fat and liver and fat-to-body massratio (ZL only) in the VAD rats are also lower than those inthe VAS ones [116] This demonstrates that VA status affectsplasma TG levels in both ZF and ZL rats and the obesitydevelopment in ZF rats This phenomenon may be caused by

the combination of VA deficiency and hypoinsulinemia sinceinsulin secretion is impaired in the VAD rats [194]

32 The Development of Hypertriglyceridemia inPatients Receiving Retinoic Acid-Based Treatments

321 The Uses of RA-Based Medicines in Clinic RA-basedmedicines tretinoin (all-trans RA) isotretinoin (13-cis RA)and alitretinoin (9-cis RA) have been used in clinic to treatdiseases such as acute promyelocytic leukemia and skindisorders [11] In fact isotretinoin has been widely used totreat severe acne Early clinical observations indicate that themedical use of isotretinoin in human subjects results in theelevation of their plasma TG levels [195ndash197] A significantportion of patients with acne receiving isotretinoin treatmentdeveloped hypertriglyceridemia [9 10] In addition thesystemic administration of isotretinoin in patients with acneresulted in the elevation of plasma levels of alanine amino-transferase (ALT) and aspartate aminotransferase (AST)indicating the liver damage [198]The hypertriglyceridemia isalso associated with reduced insulin sensitivity and elevatedTG in the very-low-density lipoprotein (VLDL) fraction[195] The treatment of all-trans RA resulted in body massgain and hypertriglyceridemia in patients with acute promye-locytic leukemia [199 200] Moreover RA treatment alsoraises plasma TG levels in rats [201ndash203]

322 The Mechanism of RA-Mediated Hypertriglyceridemiain Patients Apo CIII is produced from liver and consideredan inhibitor of LPL activity [204] Mice with Apoc3 geneknockout have hypotriglyceridemia and enhanced in vivoVLDL-TG clearance [205] On the other hand transgenicmice with overexpression of apo CIII develop hypertriglyc-eridemia [206] The RA-induced hypertriglyceridemia hasbeen attributed to RA-induced apo CIII expression

In healthy human subjects isotretinoin treatment causesa rise of plasma apo CIII protein level [207]This is caused bythe induction of Apoc3 mRNA via the activation of RXR ata RARE in its promoter [207] The plasma TG levels in ratstreated with RXR-specific agonist (LG100268) are inducedrapidly and constantly [208] This results in the reducedactivity of LPL in the heart and skeletal muscle of thoseanimals [208] The RARE is identified in the C3P regionwhich controls the hepatic specific expression of Apoc3 gene[75] Interestingly the same site is also considered to beresponsible for mediating the effects of HNF4120572 and COUP-TFII onApoc3 gene expression [209]The expression ofApoc3seems to be regulated differently by the C3P-binding proteins[75]

It is worth to note that insulin suppresses Apoc3 mRNAexpression in STZ-induced diabetic mice [210] In additionthe activation of RXR by LG100268 treatment induces insulinsensitivity and reduces TG levels in obese and diabetic mice[211] The understanding of the regulatory mechanism thatintegrates hormonal and nutritional signals at the regulatorysites such as C3P in Apoc3 promoter will shed some lightson the regulation of hepatic lipid homeostasis It will also

10 ISRN Hepatology

provide a novel target for the treatment of the RA-inducedhypertriglyeridemia

323 The Effects of RA Treatment on Obesity Developmentin Mice Interestingly the RA administration in rodentscauses reduction of body mass as summarized in [212] Thiskind of reduction of body mass has been associated withenhancement of insulin sensitivity in genetic [213] or DIOmice [108] The mechanisms of RA-mediated attenuation ofinsulin resistance have been thought to be the induction ofenergy expenditure through PPAR120573120575 activation [108] andthe inhibition of adipogenesis throughRXR120574 activation [109]On the other hand retinol can be metabolized in adipose tis-sues [214]Themice with deletion ofRaldh1 gene (Raldh1minusminus)have elevated retinal in their adipose tissues and are resistantto diet-induced obesity and insulin resistance [26] This hasbeen attributed to the suppression of adipogenesis by retinal-inhibited activation of PPAR120574 and RXR [26] It is interestingto note that either retinal or RA can inhibit the adipogenesisand cause the improvement of insulin sensitivity in micebased on these studies

33 Roles of VA and Retinoids in the Regulation of HepaticLipogenic Gene Expression Insulin resistance diabetes andother metabolic abnormalities are associated with profoundchanges of hepatic lipid and glucose metabolismThis can beattributed at least in part to the altered expression of genesinvolved in glucose and lipid metabolism [215] The hepaticlipogenesis contributes to the homeostasis of FAs and TGs

331 The Regulation of Hepatic Srebp-1c Expression by VAStatus and Retinoids Treatment Insulin plays an essentialrole in the hepatic FA synthesis It has been known for a whilethat insulin is needed for the glucose usage for lipogenesis andCO2production in the liver [216] The hepatic FA synthesis

rises sharply and continuously after rats are fasted and thenrefed a high-carbohydrate diet [217] The amount of fattyacid synthase (FAS) is induced in normal rats refed a high-carbohydrate diet after fasting and in STZ-induced diabeticrats after insulin administration [218] In the insulin-deficientrats the induction of FAS after refeeding occurs only wheninsulin injection is injected [219] a process attributed to theinduction of FAS gene (Fas) [220 221]

The transcription of hepatic Fas is controlled by a tran-scription factor named SREBP-1c [222] In the liver-specificSrebp-1c knockoutmouse liver the induction of Fas and otherlipogenic genes by refeeding after fasting is blunted [223]Interestingly insulin also specifically induces the Srebp-1cexpression in the liver [224] via two liver X receptor elements(LXREs) and one sterol-responsive element (SRE) [225]However in liver-specific insulin receptor knockoutmice theinduction of hepatic Srebp-1c by refeeding largely remainedunchanged [226] This suggests that nutrient-derived signalsmay activate downstream of insulin receptor signaling path-way to regulate Srebp-1c expression and hepatic lipogenesis[226]

As stated in the previous section my research group hasobserved that the VAD ZL and ZF rats have lower plasma TG

levels than their VAS controls [116] This is accompanied bythe reduction of the hepatic expression of Srebp-1cmRNA inVA-deficient animals [116] My research group has reportedfor the first time that retinoids synergize with insulin toinduce the expression of Srebp-1c in primary rat hepatocytes[227] Further analysis of the Srebp-1c promoter reveals thatthe previous identified LXREs responsible for mediatinginsulin-induced Srebp-1c expression are also RAREs [227]These observations show that retinoids (nutritional) andinsulin (hormonal) signals converge to regulate the FAsynthesis in the liver

332 The Effects of VA Catabolism on the Regulation of Srebp-1c Expression in Primary Rat Hepatocytes More recentlyretinoids have been proposed to play roles in glucose and lipidmetabolism and to maintain energy homeostasis [228 229]VA (retinol) is reversibly converted into retinal and retinalis irreversibly converted into RA [23] Retinal the precursorof RA production is able to synergize with insulin to inducethe Srebp-1c expression in primary rat hepatocytes [227]This suggests that the dynamic production of RA influencesthe expression of hepatic lipogenic genes It has led us toinvestigate the roles of RA production in the insulin-resistantanimals

In the liver of the Raldh1minusminus mice RA production isreduced in response to a load of retinol [230] The Raldh1minusminusmice are resistant to the development of obesity and insulinresistance after being fed an HFD [26] This is attributed tothe elevation of retinal content due to the lack of conversionof retinal to RA in the adipose tissues of the Raldh1minusminusmice Additionally the liver of the Raldh1minusminus mice hasaltered regulation of the genes for gluconeogenesis andsignificantly attenuated hepatic TG synthesis indicating theimportant role of hepatic VAmetabolism in glucose and lipidhomeostasis [231]

The hepatic expression levels of RALDH1 and RALDH2are induced in mice fed a high-cholesterol diet [232] SREsare located in the promoters of these two genes whichare induced by SREBP-1c overexpression The expression ofSrebp-1c is induced by the oxysterols derived from the high-cholesterol diet [232] This research work demonstrates theinteraction of cholesterol and RA metabolism in the liver Inaddition it has been shown that the level of Raldh1mRNA iselevated in the kidney of dbdb mice [233] Both dbdb miceand ZF rats develop obesity due to the mutation of leptinreceptor [234]

In an attempt to understand the roles of VA metabolismin the states of metabolic diseases we have compared theexpression levels of enzymes responsible for the productionof retinal and RA in the freshly isolated and cultured primaryhepatocytes from ZL rats and ZF rats [45] We have foundthat in the primary rat hepatocytes the enzymes responsiblefor the conversions of retinol to retinal and from retinal toRA are most likely RDH2 and RALDH1 respectively Theexpression levels of Raldh1 mRNA and its protein are higherin hepatocytes from ZF rats than in those from ZL rats[45] When overexpressed RALDH1 introduces the retinal-mediated induction of Srebp-1c in INS-1 cells which do not

ISRN Hepatology 11

respond to retinal in our previous study [227] These resultsindicate that insulin-resistant animals such as ZF rats mayhave alterations in retinoids metabolism

Thus we have hypothesized that the change of RAproduction from the oversupply of dietary VA due to thehyperphagia of ZF rats results in higher Srebp-1c expressionin ZF hepatocytes [45] The elevated SREBP-1c expressioncan further induceRaldh1 expression to create a feed-forwardmechanism that could be one of the reasons responsible forthe increased lipogenesis in the liver of ZF rats All of theseobservations indicate the potential roles of RA metabolismin the development of obesity and insulin resistance whichdeserves to be further studied

4 VArsquos Roles in Mediating Hepatic InsulinAction and Insulin Resistance

41 Insulin and Its Signal Transduction The insulin moleculeis made of two chains linked by one intra- and one interchaindisulfide bonds [235] The insulin receptor is a transmem-brane and heterotetramer tyrosine kinase receptor (two 120572and two 120573 subunits) linked by disulfide bonds as well [236]The binding of insulin to its receptor causes conformationchanges and transphosphorylation of the 120573-subunit tyrosinekinase [237 238] which initiates the signal transduction[239] Protein-protein interactions are involved in the trans-duction of insulin signalThe signal is transduced bymultiplecomponents in a complex network containing cascades ofkinases and phosphatases [240 241] The first intracellularcomponents mediating insulin signals are insulin recep-tor substrates (IRSs) protein molecules phosphorylated byinsulin receptor 120573-subunit and mediating insulin signals[242]

The insulin signal event is further amplified byphosphatidylinositide 3-kinases (PI3K)protein kinaseB (PKBAkt) pathway and GRB2mitogen-activated proteinkinase (MAPK) pathway [243ndash245] Another serinethre-onine kinase that can be activated by PI3K is the atypicalprotein kinase C [246] Human liver expresses severalprotein-tyrosine phosphatases (PTPs) [247] Okadai acid aninhibitor of protein phosphatase type 2A and type 1 inhibitsglycogen synthesis and insulin-stimulated Gck expression inprimary rat hepatocytes indicating that dephosphorylationmechanism may also participate in mediating insulinsignaling [248] These components are shared by insulin-likegrowth factor (IGF) receptor and involved in mediatinginsulin and IGF signals [249]

42 Metabolic Diseases and Insulin Resistance The rise ofthe number of people with one or more metabolic diseasessuch as obesity and diabetes in the world has become apublic health problem [250] The interactions of genetic andenvironmentalnutritional factors may be responsible for thecurrent rise of metabolic diseases The long evolutionaryprocess has equipped human and animal bodieswith a varietyof regulatory mechanisms controlling these interactions [251252] Human diets contain not only energy derived frommacronutrients but also micronutrients and other factors

which may influence the metabolic outcomes The roles ofindividual micronutrients in the development of metabolicdiseases are still unrevealed

One common property of human obesity and NIDDMis insulin resistance in which a given amount of insulinproduces less than normal physiological responses Dietaryfactors and manipulations have been considered to play arole in the development of insulin resistance in humans andanimals For example feeding an HFD to young and insulin-sensitive subjects for two days causes the development ofglucose intolerance [253] In the skeletal muscle of rats fedan HFD for 8 weeks the insulin-induced glucose uptakeis impaired [254] FFAs have been considered the factorsresponsible for HFD-induced leptin and insulin resistance[255ndash257]

43 Hepatic Insulin Resistance and Vicious Cycle The liverplays an essential role in the control of glucose andlipid homeostasis It coordinately regulates the processesin responses to nutritional and hormonal stimuli Insulinplays a major role in directing the liverrsquos metabolic status[258] which is partially attributed to the regulation of theexpression of genes involved in hepatic glucose and lipidmetabolism [215 259]

Insulin controls the expression of a variety of genesinvolved in glycolysis glycogenesis and lipogenesis andgluconeogenesis in the liver [145] Generally hepatic lipidand glucose metabolism is altered with the development ofinsulin resistance in obesity and NIDDM [258] This canbe reflected in the expression of insulin-regulated hepaticgenes for glucose and FA metabolism When the liver isinsulin sensitive insulin stimulates lipogenesis and inhibitsgluconeogenesis For example to regulate hepatic glucosehomeostasis insulin increases the expression of Gck gene[119 120] and Srebp-1c [224] a family member of SREBPswhich regulate the hepatic cholesterol and FA biosynthesisand their homeostasis [260] It suppresses the expressionof Pck1 [142] and G6pc [145] which control the first andlast steps of gluconeogenesis respectively When the liver isinsulin resistant insulin no longer inhibits gluconeogenesisHowever the liver still keeps the elevated lipogenesis Theelevated FA biosynthesis in the insulin-resistant state furtherfacilitates insulin secretion from pancreatic 120573-cells whichprobably enhances lipogenesis and results in a vicious cycle[113 261] The coexistence of the hepatic insulin resistanceand sensitivity at the gene expression level has been observedin rodent obese and diabetic models [215 258] Howeverthe mechanism of this coexistence of insulin sensitivity andresistance has not been revealed [261]

Recently the SREBP cleavage-activating protein gene(Scap) an escort protein necessary for generating nuclearforms of SREBPs has been knocked out in insulin-resistantobob mice [262] Deficiency of hepatic Scap reverses liverlipogenesis and steatosis in obobmice However the plasmalevels of glucose and insulin and the hepatic expression levelsof Pck1 andG6pcwere not different between the control obobmice and the obob mice with liver-specific Scap knockout[262] It seems that the suppression of hepatic FA synthesis

12 ISRN Hepatology

is not sufficient to correct insulin resistance Whether otherfactors play a role in the hepatic insulin resistance is still anopen question

The clinical use of RA-based medicine such asisotretinoin (13-cis RA) caused elevation of plasma TGlevels in human subjects [195ndash197] This increase in plasmaTG levels is also observed in rats [201ndash203] From our VAstatus studies we have shown that VA status affected theobesity development in ZF rats and reduced plasma insulinand TG levels in ZL and ZF rats suggesting improvement ofinsulin sensitivity [116] The hepatic expression of Srebp-1cwas reduced in VA-deficient animals [116] RA synergizeswith insulin to induce the expression of Srebp-1c in primaryrat hepatocytes [227] On the other hand RA treatmentinduces Pck1 expression and attenuates insulin-mediatedsuppression of its expression in primary rat hepatocytes [172]All of these observations demonstrate that RA attenuatesinsulin action (insulin-suppressed Pck1 expression) andstill promotes insulin action (insulin-induced Srebp-1cexpression) in the same primary hepatocytes

44 Possible Mechanism by Which RA Production Causes theDevelopment of the Vicious Cycle in Hepatocytes Could RAor other metabolites from VA catabolism be a factor thatcontributes to the hepatic insulin resistance and the viciouscycleUsing the regulation ofPck1 and Srebp-1c as themodel Ihave come upwith the following scheme to show that retinoidmetabolism could be a factor that causes the vicious cycle inthe liver As shown in Figure 3(a) in insulin-sensitive hepa-tocytes RA derived from retinal coordinates with insulin toregulate the expression of Srebp-1c and Pck1 The SREBP-1cprotein is processed to mature form a step that can be facili-tated by insulin [263] The mature form of SREBP-1c entersinto the nucleus and induces the mRNA levels of Raldh1and Fas which are respectively transcribed into RALDH1and FAS RALDH1 catalyzes the conversion of retinal to RAFAS catalyzes the synthesis of palmitate which is esterifiedinto TGs or elongated to longer FAs The Pck1 mRNA isused to translate into PEPCK-C protein which contributesto glucogenogenesis In the insulin-resistant hepatocytes asshown in Figure 3(b) the elevation of Raldh1 expressiondue to leptin deficiency [45] or induction of SREBP-1c byhigh-cholesterol feeding [232] induces the production of RAThe elevated RA levels will stimulate the transcription ofSrebp-1c and Pck1 This leads to more production of SREBP-1c and its mature form in the presence of higher insulinlevels in the insulin-resistant state The induction of SREBP-1c further enhances the transcription of Raldh1 and Fas andtheir corresponding proteins for the production of moreRAs and FAs respectively The RA production and SREBP-1c expression form a feed-forward cycle which causes moreTG and RA production in the insulin-resistant liver At thesame time more of the PEPCK-C protein is generated dueto the elevated Pck1 transcription by RA stimulation whichis not responsive to insulin inhibition as we have shown in[172] This leads to elevated gluconeogenesis in the insulin-resistant liver Eventually the phenotypes appear as if insulin

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1cRetinal

RALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(a) Insulin-sensitive hepatocytes

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1c

RetinalRALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(b) Insulin-resistant hepatocytes

Figure 3 The effects of RA on the insulin-regulated Srebp-1cand Pck1 expression levels the protein levels of SREBP-1c theexpression levels of Raldh1 and Fas and the fatty acid synthesisand gluconeogenesis in insulin-sensitive (a) and insulin-resistant (b)hepatocytes Please see the text in this paper for description Uparrows next to the text indicate induction The intensified weight ofthe lines indicates the induction of that part of the pathway

no longer suppresses gluconeogenesis while it still stimulatesFA synthesis in the insulin-resistant state

5 Perspectives and Future Directions

I have proposed a mechanism by which VA metabolismcontributes to the development of hepatic insulin resistanceIt explains some observations reported in the previous studiesof rodent obese and diabetic models [215 258] However itleavesmore open questionsThefirst one iswhat the initiationfactor is So far the elevated expression of Raldh1 mRNA inthe liver has been observed in ZF rats [45] and mice fed ahigh-cholesterol diet [232] These two conditions cause a lotof physiological changes such as overfeeding in ZF rats andchange of cholesterol biosynthesis in response to the feedingof high-cholesterol diet Knocking down Raldh1 specificallyin hepatocytes is needed to answer these questions The

ISRN Hepatology 13

second question is whether RA synthesis in hepatocytesis a regulated process in response to dietary or hormonalstimulations If Raldh1 is a downstream gene of SREBP-1cit should be regulated when the SREBP-1c level changes Asthe expression of Srebp-1c responds to insulin stimulation andoxysterols the regulation of Raldh1 expression in the livershould be studied The third question is why it is RALDH1but not other RALDHs Specific inhibitors of RALDHsmay be needed to answer this question Last question iswhether we can attenuate insulin resistance by suppressingthe RALDH1 activity in the liver It has been shown thatRaldh1minusminus mice are still insulin sensitive when they are onan HFD [26] This has been attributed to the effects on theadipogenesis However the liver of those knockout mice hasreduced lipid synthesis [231] Further studies are warrantedto answer all of these questions Hopefully it can become anintervention point for the treatment of insulin resistance andmetabolic diseases

Acknowledgments

This work was financially supported by a research grantfrom Allen Foundation Inc (to Guoxun Chen) a start-up fund from the University of Tennessee at Knoxville (toGuoxun Chen) and a Scientist Development Grant fromthe AmericanHeart Association (09SDG2140003 to GuoxunChen) The author thanks his colleague Dr Lauren Gellar forreading through this paper and offering her edits

References

[1] F G Hopkins ldquoFeeding experiments illustrating the impor-tance of accessory factors in normal dietariesrdquo The Journal ofPhysiology vol 44 no 5-6 pp 425ndash460 1912

[2] K J Carpenter ldquoA short history of nutritional science part 3(1912ndash1944)rdquo Journal of Nutrition vol 133 no 10 pp 3023ndash30322003

[3] E V McCollum and M Davis ldquoThe necessity of certain lipinsin the diet during growthrdquo Journal of Biological Chemistry vol15 no 1 pp 167ndash175 1913

[4] T B Osborne and L B Mendel ldquoFeeding experiments with fat-free food mixturesrdquo Journal of Biological Chemistry vol 12 no1 pp 81ndash89 1912

[5] R D Semba ldquoOn the lsquoDiscoveryrsquo of Vitamin Ardquo Annals ofNutrition and Metabolism vol 61 no 3 pp 192ndash198 2012

[6] R Blomhoff and H K Blomhoff ldquoOverview of retinoidmetabolism and functionrdquo Journal of Neurobiology vol 66 no7 pp 606ndash630 2006

[7] A Sommer ldquoVitamin A deficiency and clinical disease anhistorical overviewrdquo Journal of Nutrition vol 138 no 10 pp1835ndash1839 2008

[8] K J Rothman L L Moore M R Singer U-S Nguyen SMannino and A Milunsky ldquoTeratogenicity of high vitamin Aintakerdquo The New England Journal of Medicine vol 333 no 21pp 1369ndash1373 1995

[9] S Bershad A Rubinstein and J R Paterniti Jr ldquoChanges inplasma lipids and lipoproteins during isotretinoin therapy foracnerdquoThe New England Journal of Medicine vol 313 no 16 pp981ndash985 1985

[10] N Rodondi R Darioli A-A Ramelet et al ldquoHigh risk forhyperlipidemia and the metabolic syndrome after an episodeof hypertriglyceridemia during 13-cis retinoic acid therapy foracne a pharmacogenetic studyrdquo Annals of Internal Medicinevol 136 no 8 pp 582ndash589 2002

[11] H-U Klor A Weizel M Augustin et al ldquoThe impact oforal vitamin A derivatives on lipid metabolism what recom-mendations can be derived for dealing with this issue in thedaily dermatological practicerdquo Journal of the German Societyof Dermatology vol 9 no 8 pp 600ndash607 2011

[12] R M Russell ldquoThe vitamin A spectrum from deficiency totoxicityrdquoThe American Journal of Clinical Nutrition vol 71 no4 pp 878ndash884 2000

[13] A C Ross B Caballero R J Cousins K L Tucker and T RZiegler Modern Nutrition in Health and Diseases 11th edition2012

[14] E H Harrison ldquoMechanisms of digestion and absorption ofdietary vitamin Ardquo Annual Review of Nutrition vol 25 no 1pp 87ndash103 2005

[15] M R Lakshman ldquoAlpha and omega of carotenoid cleavagerdquoJournal of Nutrition vol 134 no 1 pp 241ndash245 2004

[16] I Potrykus ldquoNutritionally enhanced rice to combat malnutri-tion disorders of the poorrdquo Nutrition Reviews vol 61 no 6 ppS101ndashS104 2003

[17] A Wyss ldquoCarotene oxygenases a new family of double bondcleavage enzymesrdquo Journal of Nutrition vol 134 no 1 pp 246ndash250 2004

[18] R Kawaguchi J Yu J Honda et al ldquoA membrane receptor forretinol binding protein mediates cellular uptake of vitamin ArdquoScience vol 315 no 5813 pp 820ndash825 2007

[19] P Alapatt F Guo S M Komanetsky et al ldquoLiver retinoltransporter and receptor for serum retinol-binding protein(RBP4)rdquo Journal of Biological Chemistry vol 288 no 2 pp1250ndash1265 2013

[20] A R Moise N Noy K Palczewski and W S Blaner ldquoDeliveryof retinoid-based therapies to target tissuesrdquo Biochemistry vol46 no 15 pp 4449ndash4458 2007

[21] G Duester ldquoFamilies of retinoid dehydrogenases regulatingvitamin A function Production of visual pigment and retinoicacidrdquo European Journal of Biochemistry vol 267 no 14 pp4315ndash4324 2000

[22] M Theodosiou V Laudet and M Schubert ldquoFrom carrotto clinic an overview of the retinoic acid signaling pathwayrdquoCellular andMolecular Life Sciences vol 67 no 9 pp 1423ndash14452010

[23] J L Napoli ldquoInteractions of retinoid binding proteins andenzymes in retinoidmetabolismrdquoBiochimica et BiophysicaActavol 1440 no 2-3 pp 139ndash162 1999

[24] X Chai M H E M Boerman Y Zhai and J L NapolildquoCloning of a cDNA for liver microsomal retinol dehydro-genase A tissue-specific short-chain alcohol dehydrogenaserdquoJournal of Biological Chemistry vol 270 no 8 pp 3900ndash39041995

[25] B X Wu G Moiseyev Y Chen B Rohrer R K Crouch andJ-XMa ldquoIdentification of RDH10 an all-trans retinol dehydro-genase in retinal Muller cellsrdquo Investigative Ophthalmology andVisual Science vol 45 no 11 pp 3857ndash3862 2004

[26] O Ziouzenkova G Orasanu M Sharlach et al ldquoRetinalde-hyde represses adipogenesis and diet-induced obesityrdquo NatureMedicine vol 13 no 6 pp 695ndash702 2007

14 ISRN Hepatology

[27] J L Napoli ldquoPhysiological insights into all-trans-retinoic acidbiosynthesisrdquo Biochimica et Biophysica Acta vol 1821 no 1 pp152ndash167 2012

[28] G Wolf ldquoTissue-specific increases in endogenous all-transretinoic acid possible contributing factor in ethanol toxicityrdquoNutrition Reviews vol 68 no 11 pp 689ndash692 2010

[29] P V Bhat J Labrecque JM Boutin A Lacroix andA YoshidaldquoCloning of a cDNA encoding rat aldehyde dehydrogenase withhigh activity for retinal oxidationrdquoGene vol 166 no 2 pp 303ndash306 1995

[30] M Lin M Zhang M Abraham S M Smith and J LNapoli ldquoMouse retinal dehydrogenase 4 (RALDH4) molecularcloning cellular expression and activity in 9-cis-retinoic acidbiosynthesis in intact cellsrdquo Journal of Biological Chemistry vol278 no 11 pp 9856ndash9861 2003

[31] F A Mic A Molotkov X Fan A E Cuenca and GDuester ldquoRALDH3 a retinaldehyde dehydrogenase that gener-ates retinoic acid is expressed in the ventral retina otic vesicleand olfactory pit during mouse developmentrdquo Mechanisms ofDevelopment vol 97 no 1-2 pp 227ndash230 2000

[32] X Wang P Penzes and J L Napoli ldquoCloning of a cDNAencoding an aldehyde dehydrogenase and its expression inEscherichia coli recognition of retinal as substraterdquo Journal ofBiological Chemistry vol 271 no 27 pp 16288ndash16293 1996

[33] A Molotkov and G Duester ldquoGenetic evidence that retinalde-hyde dehydrogenase Raldh1 (Aldh1a1) functions downstreamof alcohol dehydrogenase Adh1 in metabolism of retinol toretinoic acidrdquo Journal of Biological Chemistry vol 278 no 38pp 36085ndash36090 2003

[34] G Elizondo J Corchero E Sterneck and F J GonzalezldquoFeedback inhibition of the retinaldehyde dehydrogenase geneALDH1 by retinoic acid through retinoic acid receptor 120572and CCAATenhancer-binding protein 120573rdquo Journal of BiologicalChemistry vol 275 no 50 pp 39747ndash39753 2000

[35] G Elizondo I M Medina-Dıaz R Cruz F J Gonzalez and LVega ldquoRetinoic acid modulates retinaldehyde dehydrogenase 1gene expression through the induction of GADD153-CEBP120573interactionrdquo Biochemical Pharmacology vol 77 no 2 pp 248ndash257 2009

[36] K Fujiwara M Kikuchi K Horiguchi et al ldquoEstrogen receptoralpha regulates retinaldehyde dehydrogenase 1 expression in ratanterior pituitary cellsrdquo Endocrine Journal vol 56 no 8 pp963ndash973 2009

[37] K Fujiwara F Maekawa M Kikuchi S Takigami T Yadaand T Yashiro ldquoExpression of retinaldehyde dehydrogenase(RALDH)2 and RALDH3 but not RALDH1 in the developinganterior pituitary glands of ratsrdquo Cell and Tissue Research vol328 no 1 pp 129ndash135 2007

[38] GWolf ldquoThe enzymatic cleavage of 120573-carotene still controver-sialrdquo Nutrition Reviews vol 53 no 5 pp 134ndash137 1995

[39] S Abu-Abed P Dolle D Metzger B Beckett P Chambonand M Petkovich ldquoThe retinoic acid-metabolizing enzymeCYP26A1 is essential for normal hindbrain patterning verte-bral identity and development of posterior structuresrdquo Genesand Development vol 15 no 2 pp 226ndash240 2001

[40] M A Leo S Iida and C S Lieber ldquoRetinoic acid metabolismby a system reconstituted with cytochrome P-450rdquo Archives ofBiochemistry and Biophysics vol 234 no 1 pp 305ndash312 1984

[41] MA Leo JM Lasker J L Raucy C-I KimM Black andC SLieber ldquoMetabolism of retinol and retinoic acid by human livercytochrome P450IIC8rdquoArchives of Biochemistry and Biophysicsvol 269 no 1 pp 305ndash312 1989

[42] R Quere A Baudet B Cassinat et al ldquoPharmacogenomicanalysis of acute promyelocytic leukemia cells highlightsCYP26cytochrome metabolism in differential all-trans retinoic acidsensitivityrdquo Blood vol 109 no 10 pp 4450ndash4460 2007

[43] J AWhite B Beckett-Jones Y-D Guo et al ldquocDNA cloning ofhuman retinoic acid-metabolizing enzyme (hP450RAI) identi-fies a novel family of cytochromes p450 (CYP26)rdquo Journal ofBiological Chemistry vol 272 no 30 pp 18538ndash18541 1997

[44] Y Zhang R Zolfaghari Reza and A C Ross ldquoMultiple retinoicacid response elements cooperate to enhance the inducibility ofCYP26A1 gene expression in liverrdquo Gene vol 464 no 1-2 pp32ndash43 2010

[45] Y Li Y Zhang R Li et al ldquoThe hepatic raldh1 expression iselevated in Zucker fatty rats and its over-expression introducedthe retinal-induced Srebp-1c expression in INS-1 cellsrdquo PLoSONE vol 7 no 9 Article ID e45210 2012

[46] R M Evans ldquoThe nuclear receptor superfamily a Rosetta stonefor physiologyrdquo Molecular Endocrinology vol 19 no 6 pp1429ndash1438 2005

[47] P Chambon ldquoA decade of molecular biology of retinoic acidreceptorsrdquo FASEB Journal vol 10 no 9 pp 940ndash954 1996

[48] D J Mangelsdorf and RM Evans ldquoThe RXR heterodimers andorphan receptorsrdquo Cell vol 83 no 6 pp 841ndash850 1995

[49] J E Balmer and R Blomhoff ldquoA robust characterization ofretinoic acid response elements based on a comparison of sitesin three speciesrdquo Journal of Steroid Biochemistry and MolecularBiology vol 96 no 5 pp 347ndash354 2005

[50] R Kurokawa J DiRenzo M Boehm et al ldquoRegulation ofretinoid signalling by receptor polarity and allosteric control ofligand bindingrdquo Nature vol 371 no 6497 pp 528ndash531 1994

[51] A Cvekl and W-L Wang ldquoRetinoic acid signaling in mam-malian eye developmentrdquo Experimental Eye Research vol 89no 3 pp 280ndash291 2009

[52] V Dupe M Davenne J Brocard et al ldquoIn vivo functional anal-ysis of the Hoxa-1 31015840 retinoic acid response element (31015840RARE)rdquoDevelopment vol 124 no 2 pp 399ndash410 1997

[53] A C Ross ldquoRetinoid production and catabolism role of dietin regulating retinol esterification and retinoic acid oxidationrdquoJournal of Nutrition vol 133 no 1 pp 291ndash296 2003

[54] T Moore and P D Holmes ldquoThe production of experimentalvitamin A deficiency in rats andmicerdquo Laboratory Animals vol5 no 2 pp 239ndash250 1971

[55] A C Ross and E H Harrison ldquoVitamin A and carotenoidsrdquoin Handbook of Vitamins D E McCormick R R Rucker J WSuttie et al Eds CRC Press Boca Raton Fla USA 4th edition2006

[56] A Chawta J J Repa R M Evans and D J MangelsdorfldquoNuclear receptors and lipid physiology opening the x-filesrdquoScience vol 294 no 5548 pp 1866ndash1870 2001

[57] C K Glass and M G Rosenfeld ldquoThe coregulator exchangein transcriptional functions of nuclear receptorsrdquo Genes andDevelopment vol 14 no 2 pp 121ndash141 2000

[58] A L Bookout Y Jeong M Downes R T Yu R M EvansandD JMangelsdorf ldquoAnatomical profiling of nuclear receptorexpression reveals a hierarchical transcriptional networkrdquo Cellvol 126 no 4 pp 789ndash799 2006

[59] B Mascrez M Mark W Krezel et al ldquoDifferential contribu-tions of AF-1 andAF-2 activities to the developmental functionsof RXR120572rdquo Development vol 128 no 11 pp 2049ndash2062 2001

[60] D Li T Li F Wang H Tian and H H Samuels ldquoFunctionalevidence for retinoid X receptor (RXR) as a nonsilent partner

ISRN Hepatology 15

in the thyroid hormone receptorRXR heterodimerrdquoMolecularand Cellular Biology vol 22 no 16 pp 5782ndash5792 2002

[61] F M Sladek W Zhong E Lai and J E Darnell Jr ldquoLiver-enriched transcription factor HNF-4 is a novel member ofthe steroid hormone receptor superfamilyrdquo Genes and Develop-ment vol 4 no 12 pp 2353ndash2365 1990

[62] K Yamagata H Furuta N Oda et al ldquoMutations in thehepatocyte nuclear factor-4120572 gene inmaturity-onset diabetes ofthe young (MODY1)rdquo Nature vol 384 no 6608 pp 458ndash4601996

[63] M Stoffel and S ADuncan ldquoThematurity-onset diabetes of theyoung (MODY1) transcription factor HNF4120572 regulates expres-sion of genes required for glucose transport and metabolismrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 24 pp 13209ndash13214 1997

[64] M Lehto P-O Bitzen B Isomaa et al ldquoMutation in the HNF-4120572 gene affects insulin secretion and triglyceride metabolismrdquoDiabetes vol 48 no 2 pp 423ndash425 1999

[65] G P Hayhurst Y-H Lee G Lambert J M Ward and F JGonzalez ldquoHepatocyte nuclear factor 4120572 (Nuclear receptor 2A1)is essential formaintenance of hepatic gene expression and lipidhomeostasisrdquo Molecular and Cellular Biology vol 21 no 4 pp1393ndash1403 2001

[66] U Roth K Jungermann and T Kietzmann ldquoActivation ofglucokinase gene expression by hepatic nuclear factor 4120572 inprimary hepatocytesrdquo Biochemical Journal vol 365 no 1 pp223ndash228 2002

[67] S Mandard R Stienstra P Escher et al ldquoGlycogen synthase2 is a novel target gene of peroxisome proliferator-activatedreceptorsrdquo Cellular and Molecular Life Sciences vol 64 no 9pp 1145ndash1157 2007

[68] F Rajas A Gautier I Bady S Montano and G MithieuxldquoPolyunsaturated fatty acyl coenzyme a suppress the glucose-6-phosphatase promoter activity bymodulating the DNA bindingof hepatocyte nuclear factor 4120572rdquo Journal of Biological Chemistryvol 277 no 18 pp 15736ndash15744 2002

[69] B Viollet A Kahn and M Raymondjean ldquoProtein kinase A-dependent phosphorylation modulates DNA-binding activityof hepatocyte nuclear factor 4rdquoMolecular and Cellular Biologyvol 17 no 8 pp 4208ndash4219 1997

[70] L Palanker J M Tennessen G Lam and C S Thum-mel ldquoDrosophila HNF4 regulates lipid mobilization and 120573-oxidationrdquo Cell Metabolism vol 9 no 3 pp 228ndash239 2009

[71] A Miura K Yamagata M Kakei et al ldquoHepatocyte nuclearfactor-4120572 is essential for glucose-stimulated insulin secretion bypancreatic 120573-cellsrdquo Journal of Biological Chemistry vol 281 no8 pp 5246ndash5257 2006

[72] R Bartoov-Shifman R Hertz H Wang C B Wollheim JBar-Tana and M D Walker ldquoActivation of the insulin genepromoter through a direct effect of hepatocyte nuclear factor4120572rdquo Journal of Biological Chemistry vol 277 no 29 pp 25914ndash25919 2002

[73] H Wang P Maechler P A Antinozzi K A Hagenfeldt andC B Wollheim ldquoHepatocyte nuclear factor 4120572 regulates theexpression of pancreatic 120573-cell genes implicated in glucosemetabolism and nutrient-induced insulin secretionrdquo Journal ofBiological Chemistry vol 275 no 46 pp 35953ndash35959 2000

[74] K Reue T Leff and J L Breslow ldquoHuman apolipoproteinCIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factorsrdquo Journal ofBiological Chemistry vol 263 no 14 pp 6857ndash6864 1988

[75] T Leff K Reue A Melian H Culver and J L BreslowldquoA regulatory element in the apoCIII promoter that directshepatic specific transcription binds to proteins in expressingand nonexpressing cell typesrdquo Journal of Biological Chemistryvol 264 no 27 pp 16132ndash16137 1989

[76] S N Lavrentiadou M Hadzopoulou-Cladaras D Kardassisand V I Zannis ldquoBinding specificity and modulation of thehuman apocIII promoter activity by heterodimers of ligand-dependent nuclear receptorsrdquo Biochemistry vol 38 no 3 pp964ndash975 1999

[77] T R Magee Y Cai M E El-Houseini J Locker and Y-JY Wan ldquoRetinoic acid mediates down-regulation of the 120572-fetoprotein gene through decreased expression of hepatocytenuclear factorsrdquo Journal of Biological Chemistry vol 273 no 45pp 30024ndash30032 1998

[78] A Qian Y Cai T R Magee and Y J Y Wan ldquoIdentificationof retinoic acid-responsive elements on the HNF1alpha andHNF4alpha genesrdquo Biochemical and Biophysical Research Com-munications vol 276 no 3 pp 837ndash842 2000

[79] H Nakshatri and P Chambon ldquoThe directly repeatedRG(GT)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites forRAR RXR HNF-4 and ARP-1 homo- and heterodimersrdquoJournal of Biological Chemistry vol 269 no 2 pp 890ndash9021994

[80] T Makita G Hernandez-Hoyos T H-P Chen H Wu E VRothenberg and H M Sucov ldquoA developmental transition indefinitive erythropoiesis erythropoietin expression is sequen-tially regulated by retinoic acid receptors andHNF4rdquoGenes andDevelopment vol 15 no 7 pp 889ndash901 2001

[81] T I Kambe J Tada-Kambe Y Kuge Y Yamaguchi-Iwai MNagao and R Sasaki ldquoRetinoic acid stimulates erythropoietingene transcription in embryonal carcinoma cells through thedirect repeat of a steroidthyroid hormone receptor responseelement half-site in the hypoxia-response enhancerrdquo Blood vol96 no 9 pp 3265ndash3271 2000

[82] F-J Lin J Qin K Tang S Y Tsai and M-J Tsai ldquoCoup drsquoEtatan orphan takes controlrdquo Endocrine Reviews vol 32 no 3 pp404ndash421 2011

[83] L-H Wang S Y Tsai R G Cook W G Beattie M-J Tsaiand BW OrsquoMalley ldquoCOUP transcription factor is a member ofthe steroid receptor superfamilyrdquoNature vol 340 no 6229 pp163ndash166 1989

[84] X Leng A J Cooney S Y Tsai and M-J Tsai ldquoMolecularmechanisms of COUP-TF-mediated transcriptional repressionevidence for transrepression and active repressionrdquo Molecularand Cellular Biology vol 16 no 5 pp 2332ndash2340 1996

[85] L Li X Xie J Qin et al ldquoThe nuclear orphan receptorCOUP-TFII plays an essential role in adipogenesis glucosehomeostasis and energy metabolismrdquo Cell Metabolism vol 9no 1 pp 77ndash87 2009

[86] F A Pereira Q Yuhong G Zhou M-J Tsai and S YTsai ldquoThe orphan nuclear receptor COUP-TFII is required forangiogenesis and heart developmentrdquo Genes and Developmentvol 13 no 8 pp 1037ndash1049 1999

[87] N Takamoto I Kurihara K Lee F J DeMayo M-J Tsai andS Y Tsai ldquoHaploinsufficiency of chicken ovalbumin upstreampromoter transcription factor II in female reproductionrdquoMolec-ular Endocrinology vol 19 no 9 pp 2299ndash2308 2005

[88] P Zhang M Bennoun C Gogard et al ldquoExpression of COUP-TFII in metabolic tissues during developmentrdquo Mechanisms ofDevelopment vol 119 no 1 pp 109ndash114 2002

16 ISRN Hepatology

[89] Z Xu S Yu C-H Hsu J Eguchi and E D Rosen ldquoTheorphan nuclear receptor chicken ovalbumin upstream pro-moter-transcription factor II is a critical regulator of adipogene-sisrdquoProceedings of theNationalAcademy of Sciences of theUnitedStates of America vol 105 no 7 pp 2421ndash2426 2008

[90] P Bardoux P Zhang D Flamez et al ldquoEssential role of chickenovalbumin upstreampromoter-transcription factor II in insulinsecretion and insulin sensitivity revealed by conditional geneknockoutrdquo Diabetes vol 54 no 5 pp 1357ndash1363 2005

[91] G Achatz B Holzl R Speckmayer C Hauser F Sandhoferand B Paulweber ldquoFunctional domains of the human orphanreceptor ARP-1COUP-TFII involved in active repression andtransrepressionrdquo Molecular and Cellular Biology vol 17 no 9pp 4914ndash4932 1997

[92] S A Kliewer K Umesono R A Heyman D J MangelsdorfJ A Dyck and R M Evans ldquoRetinoid X receptor-COUP-TFinteractionsmodulate retinoic acid signalingrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol89 no 4 pp 1448ndash1452 1992

[93] A J Cooney S Y Tsai BW OrsquoMalley andM-J Tsai ldquoChickenovalbumin upstreampromoter transcription factor (COUP-TF)dimers bind to different GGTCA response elements allowingCOUP-TF to repress hormonal induction of the vitamin D3thyroid hormone and retinoic acid receptorsrdquo Molecular andCellular Biology vol 12 no 9 pp 4153ndash4163 1992

[94] SW Kruse K Suino-Powell X E Zhou et al ldquoIdentification ofCOUP-TFII orphannuclear receptor as a retinoic acid-activatedreceptorrdquo PLoS Biology vol 6 no 9 Article ID e227 2008

[95] J P Berger T E Akiyama and P T Meinke ldquoPPARs thera-peutic targets for metabolic diseaserdquo Trends in PharmacologicalSciences vol 26 no 5 pp 244ndash251 2005

[96] JM Peters andF J Gonzalez ldquoSorting out the functional role(s)of peroxisome proliferator-activated receptor-120573120575 (PPAR120573120575)in cell proliferation and cancerrdquo Biochimica et Biophysica Actavol 1796 no 2 pp 230ndash241 2009

[97] A Tenenbaum and E Fisman ldquoBalanced pan-PPAR activatorbezafibrate in combination with statin comprehensive lipidscontrol and diabetes preventionrdquo Cardiovascular Diabetologyvol 11 no 1 article 140 2012

[98] O Braissant F Foufelle C Scotto M Dauca and W WahlildquoDifferential expression of peroxisome proliferator-activatedreceptors (PPARs) tissue distribution of PPAR-120572 -120573 and -120574 inthe adult ratrdquo Endocrinology vol 137 no 1 pp 354ndash366 1996

[99] H Higashiyama A N Billin Y Okamoto M Kinoshita andS Asano ldquoExpression profiling of Peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues usingtissue microarrayrdquo Histochemistry and Cell Biology vol 127 no5 pp 485ndash494 2007

[100] P S Jones R Savory P Barratt et al ldquoChromosomal local-isation inducibility tissue-specific expression and strain dif-ferences in three murine peroxisome-proliferator-activated-receptor genesrdquo European Journal of Biochemistry vol 233 no1 pp 219ndash226 1995

[101] S A Kliewer B M Forman B Blumberg et al ldquoDifferentialexpression and activation of a family of murine peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no15 pp 7355ndash7359 1994

[102] E E Girroir H E Hollingshead P He B Zhu G H Perdewand J M Peters ldquoQuantitative expression patterns of peroxi-some proliferator-activated receptor-120573120575 (PPAR120573120575) protein in

micerdquo Biochemical and Biophysical Research Communicationsvol 371 no 3 pp 456ndash461 2008

[103] P Escher O Braissant S Basu-Modak L Michalik W Wahliand B Desvergne ldquoRat PPARs quantitative analysis in adult rattissues and regulation in fasting and refeedingrdquo Endocrinologyvol 142 no 10 pp 4195ndash4202 2001

[104] D Auboeuf J Rieusset L Fajas et al ldquoTissue distributionand quantification of the expression of mRNAs of peroxi-some proliferator-activated receptors and liver X receptor-120572 inhumans no alteration in adipose tissue of obese and NIDDMpatientsrdquo Diabetes vol 46 no 8 pp 1319ndash1327 1997

[105] N ShawM Elholm andN Noy ldquoRetinoic acid is a high affinityselective ligand for the peroxisome proliferator-activated recep-tor 120573120575rdquo Journal of Biological Chemistry vol 278 no 43 pp41589ndash41592 2003

[106] G Wolf ldquoRetinoic acid as cause of cell proliferation or cellgrowth inhibition depending on activation of one of twodifferent nuclear receptorsrdquoNutrition Reviews vol 66 no 1 pp55ndash59 2008

[107] T T Schug D C Berry N S Shaw S N Travis and N NoyldquoOpposing effects of retinoic acid on cell growth result fromalternate activation of two different nuclear receptorsrdquo Cell vol129 no 4 pp 723ndash733 2007

[108] D C Berry and N Noy ldquoAll-trans-retinoic acid repressesobesity and insulin resistance by activating both peroxisomeproliferation-activated receptor 120573120575 and retinoic acid receptorrdquoMolecular and Cellular Biology vol 29 no 12 pp 3286ndash32962009

[109] D C Berry D DeSantis H Soltanian C M Croniger andN Noy ldquoRetinoic acid upregulates preadipocyte genes to blockadipogenesis and suppress diet-induced obesityrdquo Diabetes vol61 no 5 pp 1112ndash1121 2012

[110] M G Borland C Khozoie P P Albrecht et al ldquoStableover-expression of PPAR120573120575 and PPAR120574 to examine receptorsignaling in human HaCaT keratinocytesrdquo Cellular Signallingvol 23 no 12 pp 2039ndash2050 2011

[111] S E OrsquoSullivan and D A Kendall ldquoCannabinoid activationof peroxisome proliferator-activated receptors potential formodulation of inflammatory diseaserdquo Immunobiology vol 215no 8 pp 611ndash616 2010

[112] Z C Yan D Y Liu L L Zhang et al ldquoExercise reduces adiposetissue via cannabinoid receptor type 1 which is regulated byperoxisome proliferator-activated receptor-120575rdquo Biochemical andBiophysical Research Communications vol 354 no 2 pp 427ndash433 2007

[113] J D McGarry ldquoWhat if Minkowski had been ageusic Analternative angle on diabetesrdquo Science vol 258 no 5083 pp766ndash770 1992

[114] TMoore ldquoVitaminA and carotene the vitaminA reserve of theadult human being in health and diseaserdquo Biochemical Journalvol 31 no 1 pp 155ndash164 1937

[115] GWolfMD Lane and B C Johnson ldquoStudies on the functionof vitamin A in metabolismrdquo Journal of Biological Chemistryvol 225 no 2 pp 995ndash1008 1957

[116] Y Zhang R Li Y Li W Chen S Zhao and G Chen ldquoVitaminA status affects obesity development and hepatic expression ofkey genes for fuel metabolism in Zucker fatty ratsrdquoBiochemistryand Cell Biology vol 90 no 4 pp 548ndash557 2012

[117] M Singh V N Singh and T A Venkitasubramanian ldquoEarlyeffects of feeding excess vitamin A hepatic glycogen bloodlactic acid plasma nefa and glucose tolerance in ratsrdquo LifeSciences vol 7 no 5 pp 239ndash247 1968

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Hepatology 3

and direct production of RA by cleavage of 120573-carotenein a process that might not involve retinol or retinal asintermediates [38]

In hepatocytes RA can be further modified by enzymessuch as cytochrome P450 26A1 (CYP26A1) to morehydrophilic products [39ndash44] The expression of Cyp26a1mRNA is rapidly induced by RA treatment and is often usedas an indicator of RA production [45]

Other products derived from retinoid metabolism havebeen reported Retroretinoids are a class of retinol derivativesin which the polyene tail is rigidly attached to the 120573-ionone ring by a double bond with the remaining doublebonds retaining the conjugated system and extending it tothe 3 4 double bond within the ring Another bioactiveretinoid is 3 4-dihydroretinol also known as vitamin A2It is abundant in freshwater fish where it is metabolizedinto 11-cis-dehydroretinol which can serve as a ligand forvisual pigments Oxidized retinol metabolites such as 4-oxo-retinoic acid were reported to be highly active indetermining digit development and activation of retinoic acidreceptor 120573 (RAR120573) Some proteins are modified by covalentretinoylation [13]

14 Potential Transcription Factors That Mediate RA EffectsRAR Retinoid X Receptor (RXR) PPAR120573120575 HepatocyteNuclear Factor 4120572 (HNF4120572) and Chicken OvalbuminUpstream Promoter-Transcription Factors (COUP-TFs)

141 Retinoic Acid-Responsive Element (RARE) It has beengenerally believed that the active metabolite of VA RAregulates gene expression through activation of twomembersof nuclear receptors [46] RARs andRXRs [27 28] RARRXRheterodimer or RXRRXRhomodimer associatedwith RAREin the promoters activates the transcription of RA-responsivegenes upon ligand binding [47 48]

RA regulates gene expression through transcription fac-tors bound to RAREs A typical RARE contains two hex-americ motifs 51015840-(AG)G(GT)TCA-31015840 arranged as palin-dromes direct repeats (DRs) or inverted repeats (IRs) [49]These two motifs are separated by nucleotides The commonDRs with 1 2 or 5 nucleotide spacing are termed DR1 DR2and DR5 elements respectively These different DRs maydetermine the regulatory features of the RA-targeted genesWhen bound to DR2 and DR5 elements the 51015840 half-site isoccupied by RXR and the 31015840 half-site by RAR [47] On theother hand the upstream half-site of a DR1 can be recognizedby a RAR a setting that may recruit repressor complexes tosuppress gene expression When bound to DR1 elements thepolarity of the RARRXR heterodimer is inverted and thecomplex is unresponsive to RA stimulation probably dueto the inability of RAR ligands to induce the dissociationof corepressors [50] RXRs can also bind as homodimersto DR1 elements and respond to 9-cis RA By contrast forDR2DR5 elements a RAR occupies the downstream halvesof these RAREs and the complex functions as transcriptionalactivator Additional arrangement of two or three hexamericmotifs with variable spacing has also been identified [51]RARE can be found even in the 31015840 of a gene [52]

142 RARs and RXRs forMediating RAResponses Themajorfunctions of VA are mediated by its active metabolite RA Itis generally believed that all-trans and 9-cis RAs are majorisoforms that mediate the regulation of gene expression [6]However the most important ligand is probably all-transRA as the detection of 9-cis RA produced in a physiologicalsetting has been challenging [6] The RA homeostases iscontrolled by the expression of the enzymes responsible forits production and disposal [53] It is worth noting that somephysiological functions of retinol such as in vision could notbe replaced by RA treatment [54]

RARs and RXRs are members in the nuclear receptorsuperfamily [6 47 55] Nuclear receptors are transcriptionfactors that mediate a complex array of extracellular signalsinto transcriptional responses in a ligand-dependent manner[46] Other members in this family include transcriptionfactors that bind to a variety of physiological activemoleculessuch as endocrine steroids vitamin D thyroid hormone anda large number of ldquoorphanrdquo receptors whose ligands targetgenes and physiological functions were initially unknown[46 56] Upon binding to the ligands nuclear receptorsundergo conformational changes which allow them to inter-act with transcriptional cofactors and in turn regulate theexpression of their target genes [46 57]

RARs and RXRs are widely expressed in metabolic activetissues [58] There are three isoforms each for RARs (RAR120572-120573 and -120574) that bind and respond to all-trans and 9-cis RAsand for RXRs (RXR120572 -120573 and -120574) which can only bind andrespond to 9-cis RA [55] Functional studies have indicatedthat RXRRAR heterodimers act as the main functional unitstransducing RA signals in development which needs theformation of specific heterodimers such as RXR120572RAR120572RXR120572RAR120573 and RXR120572RAR120574 RARRXR heterodimersand RXRRXR homodimers modulate gene expression bybinding to RAREs located in the regulatory regions of theirtarget genes [6 47 55]

Other than RARs many nuclear receptors form het-erodimers with RXRs for binding to their cognate-responsiveelements such as thyroid hormone receptors (TRs) vita-min D3 receptors (VDRs) and PPARs [46] So far RXRsare considered binding partners for other nuclear receptorpathways The activation states of RXRs differ among theseheterodimers and seem to depend on the nature of theirpartners and the binding elements For example in the caseof RARRXR heterodimer either one can be transcriptionallyactive However the ligand-bound RXR is not active unlessits RAR partner binds to a ligand [59] Either PPARs orRXRs in a PPARRXR heterodimer can bind to their agonistsand activate transcription The presence of both ligandsresults in synergistic activation Liver X receptor (LXR)RXRheterodimer retains 9-cis RA responsiveness indicating thatRXR is active upon ligand binding [46] By contrast theTRRXR and VDRRXR heterodimers are thought to benonpermissive as they are activated by the TR ligand tri-iodothyronine (T3) and VDR ligand 125-dihydroxy-VD3(calcitriol) respectively but not by RXR-specific ligands Itis generally believed that in a nonpermissive heterodimerRXR is incapable of binding to its ligands and thus it isoften referred to as a silent partner However recent data

4 ISRN Hepatology

indicated that RXR was able to bind to ligands and leadto dissociation of corepressors from TR thus modulatingheterodimer activity [60]

143 HNF4120572 for Mediating RA Responses Originally HNF-4120572 (NR2A1 gene Nr2a1) was identified as a transcriptionfactor enriched in liver nuclear extract and was responsiblefor transthyretin gene transcription [61] HNF4120572 is a highlyconserved member of the nuclear receptor superfamilyHNF4120572 binds to DNA as a homodimer and acts as a positivetranscriptional regulator of many hepatic genes Expressionof Nr2a1 gene is driven by two distinct promoters the P1promoter that drives expression of splice variants HNF41205721-6in the liver kidney and intestinecolon and the P2 promoterthat drives expression of splice variants HNF41205727-9 in theintestinecolon stomach and 120573-cells of the pancreas Anonsense mutation (Q268X) in exon 7 of the Nr2a1 genethat caused a deletion of 187 C-terminal amino acids of theHNF4120572 protein was indentified in patients with maturity-onset diabetes of the young type I (MODY1) an autosomaldominant early-onset form of noninsulin-dependent dia-betesmellitus (NIDDM) [62]This shortenedHNF4120572 proteinlacks transcriptional activity and fails to dimerize and bind toDNA [63] Another mutation due to a 2 bp deletion in exon3 of the HNF4120572 gene which results in a truncation of theNr2a1 protein to 122 instead of 465 amino acids causes thecarriers to have significantly lower levels of plasma TG andapolipoprotein CIII (apoCIII) than normal subjects [64]

The roles of HNF4120572 have been studied extensively Liver-specific knockout of HNF4120572 resulted in the reduction ofplasma levels of TG and cholesterol accumulation of hepaticlipid contents and decrease of hepatic expression levels ofapolipoproteins AII AIV CII and CIII [65] Moreover ithas been shown that HNF4120572 can activate the expressionof hepatic glucokinase gene (Gck) after it binds to the Gckpromoter [66]

It seems that there is an interaction of PPAR120572 andHNF4120572signaling pathways In the promoter of mouse glycogensynthase 2 gene (Gys2) there are two putative PPAR responseelements (PPREs) one in the upstream promoter and onein intron 1 [67] The DR1 PPRE in the upstream promoterregion is the response element for HNF4120572 The expressionlevel of Gys2 mRNA in the liver of Nr2a1minusminus mice isdramatically lower than that of the wild-type controls Inaddition the Gys2mRNA level in the liver of Pparaminusminusmiceis also lower than that of the wild-type control mice PPAR120572ligand Wy14643 no longer induces Gys2 mRNA expressionin primary hepatocytes of Pparaminusminus mice In Hep2G cellsPPAR120572 activation significantly reduced HNF4120572-dependenttransactivation of Gys2 promoter demonstrating the interac-tion of their signaling pathways [67]

HNF4120572 although initially believed to be an orphanreceptor activity can be modulated by fatty acyl-coenzyme A(CoA) thioesters [68] and also by protein kinase A-mediatedphosphorylation [69] For drosophila HNF4 (dHNF4) regu-lates lipid mobilization and 120573-oxidation [70] Mutant larvaewith dHnf4 deletionwere unable to efficientlymobilize storedfat for energy during starvation consistent with reduced

expression of genes that control lipid catabolism and 120573-oxidation It seems that FAs released from TGs can activatedHNF4 in fasted drosophila which in turn drives FA oxida-tion for energy production [70] This suggests that HNF4120572may be responsive to dietary signals and important in thecontrol of metabolic status

It has been shown that HNF4120572 is responsible for thefunctions of pancreatic 120573-cells The pancreatic 120573-cell-specificNr2a1minusminus knockout mice have impaired glucose-stimulatedinsulin secretion [71] HNF4120572 activates the insulin geneexpression through indirect and direct mechanisms [72]HNF4120572 also regulates the expression of other pancreatic120573-cell genes involved in glucose metabolism and nutrient-induced insulin secretion including glucose transporter-2and liver-type pyruvate kinase [73]

A relationship between RA signaling pathway andHNF4120572 activation has been indicated in the regulation ofthe hepatic gene expression Multiple sites in the promoterof human apoCIII (APOC3) are responsible for positive andnegative regulation of its transcription in HepG2 cells andthe proximal sequence of a 13-nucleotide element for thepositive regulation of the APOC3 transcription is identicalbetween human and rat genomic sequences [74] It has beenshown that different proteins or forms of the same proteinin the nuclear extract from HepG2 and Hela cells bound tothe same 13-nucleotide sequence element in the promoterof the APOC3 gene [75] The activity of this element is notaffected by its orientation in a reporter construct [75] Theproximal hormone-responsive element B (minus87minus72) bindsstrongly to HNF4 ARP1COUP-TFII EAR2COUP-TFIIIEAR3COUP-TFI and RXR120572RAR120572 heterodimers and lessefficiently to homodimers of RAR120572 and heterodimers ofRXR120572with TR120573 or PPAR120572 [76] InHep3B cells the treatmentof RA caused the reduction ofNr2a1mRNA [77] and HNF4120572protein levels after the RA treatment for 3 days [78]

It was found that RA-mediated downregulation of 120572-fetoprotein gene is dependent on the inhibition of HNF1and HNF4120572 in Hep3B cells [77] Since there is no RARE atthe Nr2a1 gene promoter the mechanism for RA-mediatedinhibition of HNF4120572 remains to be investigated On the otherhandHNF4120572 regulates retinoidmetabolism by activating thetranscription of CRBPII gene [79] Furthermore it has beensuggested that HNF4120572 and RXR120572 compete for occupancyof the same site in erythropoietin gene (Epo) promotersequentially regulating its expression during embryogenesis[80] In the development of mouse embryo the hepaticexpression of erythropoietin is sequentially regulated byRARs and HNF4120572 at days E1025 and E1225 respectively[80] This DR2 RARE is in the 31015840 hypoxia-response enhancerof Epo gene and is responsible for RA-mediated inductionof Epo gene in P19 and F9 embryonal carcinomas but not inHep3B cells [81]

144 COUP-TFII for Mediating RA Responses Chicken oval-bumin upstream promoter-transcription factors (COUP-TFs) are members of a family of evolutionarily con-served orphan nuclear receptor without known physio-logical ligand Currently this family has three members

ISRN Hepatology 5

COUP-TFINR2F1ErbA-related protein-3 (EAR3) COUP-TFIINR2F2apolipoprotein-AI regulatory protein-1 (ARP1)and COUP-TFIIINR2F6 (EAR2) [82] COUP-TFs are con-servative among all species with the ligand-binding domainsof COUP-TFI or -II being identical in vertebrates

The cloning and analysis of COUP-TFII (gene NR2F2)cDNA from Hela cells indicate that it is a member ofnuclear receptor superfamily [83] COUP-TFII seems to berequired earlier in the development processes than COUP-TFI COUP-TFII has been thought to suppress gene expres-sion [84] It has been shown to function in a variety of biolog-ical processes such as development cellular differentiationgrowth and metabolic homeostasis [85] Deletion of Nr2f2in mouse is lethal [82] It has been shown that mice withhomozygous deletion of Nr2f2 die at around E10 probablydue to severe hemorrhage and edema and only one-thirdof the heterozygote mice survive before weaning [86] Nr2f2heterozygous pups have growth retardation in comparisonwith their wild-type controls [87] Adult Nr2f2 heterozygousknockout mice have lower body weight and basal plasmainsulin level but higher insulin sensitivity than that of theirwild-type controls [85] They also exhibit resistance to high-fat diet- (HFD-) induced obesity and improved glucosetolerance [85]

COUP-TFII expression can be detected in a variety ofmetabolic active tissues and organs [88] Since heterozygousmice withNr2f2 deletion have improved glucose homeostasisand increased energy expenditure this indicates that COUP-TFII also plays roles in white adipose tissues developmentand energy metabolism [85] COUP-TFII may suppressadipogenesis via inhibiting the expression of genes foradipocyte differentiation such as the expression of sterolregulatory element-binding protein-1c (SREBP1c) PPAR120574and CCAATenhancer-binding protein 120572 (CEBP120572) [89]COUP-TFII regulates the expression of insulin gene andseveral other genes involved in glucose and lipid metabolismin pancreatic 120573-cells Heterozygous mice with Nr2f2 deletionin pancreatic 120573-cells have impaired glucose sensitivity andabnormal insulin secretion [90]

COUP-TFII regulates gene expression via both protein-protein and protein-DNA interactions [76] For exampleCOUP-TFII binds to hormone response elements (HREs)recognized by other nuclear receptors and in turnmodulatesthe expression of these genes It has been shown that COUP-TFII can bind to a variety of HREs that contain direct orinverted imperfect AGGTCA repeats with various spacesCOUP-TFII can also interact with the common partners orgeneral transcriptional factors to modulate gene expression[84 91] For example the amount of RXR available for theformation of high-affinity DNA-binding complexes of thethyroid hormoneRAR subfamily can be limited COUP-TFIIcan also actively silence basal and activated transcriptionlikely through direct interaction with TFIIB or other generaltranscription factors [84]Therefore COUP-TFII may antag-onize the functions of other hormones and in turn alter thecellular responses to multiple-hormone signaling pathwaysand it can have profound effects on metabolic homeostasis

COUP-TF protein interacts with RXR120572 to form het-erodimer [92] Using RXR120572 cDNA probe COUP-TFs were

identified to bind to RAREs The original COUP-TF-bindingsite in the ovalbumin gene is also a RARE that is repressedby COUP-TF [93] On the other hand RXR120572 and COUP-TFII can bind to the same DR1 element individually or inthe heterodimeric form in an electrophoresis mobility shiftassay (EMSA) Cotransfection of COUP-TFII and RXR120572suppresses RXR-mediated activation of CRBPII promoterwhich contains one RARE [92] COUP-TFs are involved inthe modulation of RAR- and RXR-mediated responses toretinoids during embryogenesis [84] Recently COUP-TFIIhas been identified as a low-affinity RA receptor The ligandbinding of COUP-TFII is in an autorepressed conformationAt high concentrations RA is able to promote COUP-TFIIto recruit coactivators and to activate a COUP-TF reporterconstruct [94] These observations suggest a linkage betweenRA and COUP-TFII signaling pathways

145 PPAR120573120575 forMediating RAResponses PPARs aremem-bers of nuclear receptor superfamily They take part in theregulation of a variety of physiological functions such as celldifferentiation metabolism and immune functions [95] Sofar three PPAR isoforms PPAR120572 PPAR120573120575 and PPAR120574are identified and reported The expression of PPAR120573120575 isubiquitous which can be detected in a lot of cell typesand tissues [96 97] In rats PPAR120573120575 mRNA and proteinsare expressed ubiquitously and often coexpressed with otherPPARs [98] Similar expression profiles are observed inmice [99ndash101] In mice PPAR120573120575 protein can be detectedin a variety of tissues with high expression levels in thesmall intestine skin and liver [102] The expression levels ofPPAR120573120575mRNA and protein in the liver of rats fasted for 12hours are reduced and increased upon refeeding for 45 hours[103]The expression of low levels of human PPAR120573120575mRNAcan be detected in the adipose tissues the skeletal muscle theliver the kidney and the intestines [104]

It has been shown that RA is a high-affinity ligand(nanomolar range) for PPAR120573120575 activation in COS-7 cells[105] RA-mediated activation of PPAR120573120575 plays a role incell proliferation [106] In certain types of cells RA isrespectively delivered to RAR and PPAR120573120575 by cytosolretinoic acid-binding protein II (CRABP-II) and fatty acid-binding protein 5 [107] The activation of these two receptorsby RA has opposite effects on cell growth RA can activatePPAR120573120575 in preadipocytes and mature adipocytes [108 109]RA treatment prevents obesity development in diet-inducedobesity (DIO) via increase of lipolysis [108] and inhibition ofadipocyte differentiation [109]

However when human PPAR120573120575 was stably over-expressed in human keratinocyte cells no change inPPAR120573120575 target gene expression could be observed after thetreatment of RA [110] Many studies have shown that endo-cannabinoids regulate the activity of PPARs via direct andindirect mechanisms [111] The expression of endocannabi-noid receptor type 1 (CB1) is reduced upon overexpressionof PPAR120573120575 suggesting other pathways that PPAR120573120575 isinvolved in [112]

In summary retinol in hepatocytes can be either storedas REs or oxidized into retinal as shown in Figure 1 RA

6 ISRN Hepatology

HepatocyteCell membrane

RE Retinol Retinal RA

Other metabolic pathwaysNuclear

membrane

Cytosol RAOther ligands

RARRXR PPAR120573120575

COUP-TFII UpdownmRNAHNF4120572HNF4120572

RARE

Nucleus

Figure 1 The effects of RA production and other metabolicfactors on the activities of transcription factors associated with aretinoic acid-responsive element (RARE) in the promoter of anRA-targeted gene In primary hepatocytes RA is produced fromretinal derived from retinol Retinol can be esterified into retinylester (RE) or oxidized into retinal The RARE can be occupied byretinoic acid receptor (RAR) retinoid X receptor (RXR) hepatocytenuclear factor 4120572 (HNF4120572) chicken ovalbumin upstreampromoter-transcription factor II (COUP-TFII) and peroxisome proliferator-activated receptor 120573120575 (PPAR120573120575) in the forms of heterodimers orhomodimers These transcription factors receive signals from RAand metabolic pathways and regulate the expression of the RA-responsive gene

is dynamically produced and sent to nucleus where itinteracts with transcription factors associated with RAREin the enhancer regions of the RA-responsive genes Sofar the transcription factors that can be associated with aparticular RARE include RAR RXR COUP-TFII HNF4120572and PPAR120573120575 They form heterodimers or homodimers andbind to RARE to regulate the transcription rate of that geneThe nuclear receptors that occupy the RARE at any givenmoment may be determined by the VA status of the animaland the developmental differentiation and metabolic statesof hepatocytes These transcription factors integrate signalsfrom RA and other metabolic pathways to control the geneexpression positively and negatively Other metabolic signalsin combination with RA may affect the occupancy of thenuclear receptors bound to the RARE and their activationsand may in turn alter the outcomes of the RA-mediatedtranscription responses

2 VArsquos Roles in Glucose Metabolism

As a convenient energy source glucose can be used by all cellsthat are in charge of different physiological functionsGlucoseis metabolized differently in response to hormonal and nutri-tional statuses [113] Hepatocytes utilize and produce glucosedepending on the physiological needs and feeding status ofa subject These processes are regulated by nutritional andhormonal stimuli VA status has been implied to play a role

21 The Effects of VA Status on Hepatic Glycogen ContentsThe roles of VA in glucose metabolism had been suggestedIn 1937 the liver samples of patients who died of diabetesshowed an elevation of VA contents [114] When rats werefed a VA-deficient (VAD) diet to induce VA deficiency theirliver glycogen content was depleted [115] Since VA deficiencyalso caused reduction of food intake in the VAD rats a pair-feeding control group was included The pair-fed rats withequal energy intake as that of VAD rats had higher hepaticglycogen content [115] This depletion of hepatic glycogencontent was attributed to the reduction of glycogenesisfrom trioses rather than directly from glucose [115] Thephenomenon of the depletion of hepatic glycogen contentin the liver of VAD rats has also been observed recently inmy lab [116] On the other hand when rats were fed a dietwith excessive amounts of VA for two days an elevation ofthe hepatic glycogen content in the liver after fasting wasobserved [117] It seems that hepatic VA content is directlycorrelated with the hepatic glycogen content

22 The Effects of Animal VA Statuses and Retinoids onHepatic Gck Expression To initiate the hepatic glucose uti-lization glucose is phosphorylated into glucose 6-phosphateby hexokinases in the first reaction of glycolysis So far fourhexokinase isozymes hexokinase I (A) II (B) III (C) andIV (D) have been identified They have different tissue dis-tributions intracellular locations and kinetic characteristicsMammalian hexokinase IV (D) is also known as glucokinase(GK) (ATP d-hexose 6-phosphotransferase EC 2711) [118ndash121] Mutations of GK have been associated with MODY[122] GK has two unique features that differentiate it fromother hexokinase family members It has low affinity forglucose (higher Km) and it is insensitive to allosteric inhi-bition mediated by physiological concentrations of glucose6-phosphate whereas other hexokinases are sensitive to it[118 121 123 124] In addition to glucose other substrates ofGK include fructose mannose and 2-deoxyglucose [118]

Generally GK activity is mainly observed in the liverand pancreatic islets The 120573-cells and liver GK isoforms havesimilar kinetic properties [125 126] In the short term theGK activity can be regulated via allosteric interactions andcovalent modifications such as binding to GK regulatoryprotein [127] phosphorylation by protein kinase A [128] andinteractionwith a cytosolic GK-associated phosphatase [129]

The long-term regulation of GK activity is done throughthe transcription of its gene Gck which is differentiallyregulated by an upstream promoter in pancreatic 120573-cells anda downstream promoter in hepatocytes [130 131] Using astrain of transgenic mice containing the cDNA of humangrowth hormone gene driven by an upstream Gck promoterfragmentGck expression has been found in certain neuroen-docrine cells of the pancreas pituitary brain gut thyroidand lungs [132] Activation of the upstream or downstreampromoter leads to the generation of a Gck mRNA with aunique 51015840 sequence derived from exon 1120573 or 1L respectivelySince the translation initiation coden is located in the firstexon the GK proteins encoded by the different transcriptsdiffer in the first 15 amino acids at the amino terminus

ISRN Hepatology 7

[130 131] The mechanisms by which the upstream and thedownstream promoters are selectively activated in differentcells have not been revealedThe temporal and special controlof the promoter selectionmust be determined by signals fromdifferentiation and development processes

The upstream and downstream promoters are activatedbased on the hormonal and nutritional conditions of thesubject For example the hepatic but not the pancreatic 120573-cell Gck expression is reduced while fasting and increasedwhile refeeding [130] In the rat liver insulin and glucagonrespectively induce and inhibit the expression of GckmRNA[133ndash135] A long-standing question in the field is the insulin-responsive element (IRE) responsible for the insulin-inducedhepaticGck expression Using the reporter gene constructs tostudy insulin-induced Gck promoter activation has not beensuccessful For example a reporter gene construct containinga fragment of 55 kb hepatic Gck promoter failed to showany response to insulin treatment in rat primary hepatocytes[136] This suggests that the IRE of the hepatic Gck mightbe in an area not included in this 55 kb promoter fragmentAlternatively the unresponsiveness to insulin of the reportergene constructs in the experimental settings could be due tothe short-lived signal from insulin for Gck transcription aswe have shownpreviously [137] Interestingly the hepatocyte-specific enhancer region that controls the activation of liver-specific promoter has been located in the region from minus1003to minus707 relative to the transcription initiation site in primaryrat hepatocytes By contrast this region acts as a silencer inFTO-2B hepatoma cells and has no effects on insulinomacells [138] Further studies are needed to identify the insulin-responsive element in the hepatic Gck promoter

The direct effects of RA on the expression of Gck mRNAin primary rat hepatocytes have been studied Previouslyothers have shown that all-trans RA induced Gck expressionin primary rat hepatocytes However nonadditive effect ofRA on insulin-induced Gck expression was observed [139140] Recently we have shown that retinoids synergized withinsulin to induce Gck expression in primary rat hepatocytes[137] We have observed that all-trans retinol retinal and RAare able to synergize with insulin to induce Gck expressionprobably via the activation of RARRXR in primary rat hepa-tocytes In addition VA status also controls the expression ofhepatic Gck expression [137] The levels of Gck mRNA [116]and its activity [137] in the liver of VAD rats are lower thanthose of VA-sufficient (VAS) controls In addition a singletreatment of RA increases the hepatic Gck expression in rats[137]

23 The Effects of Animal VA Status and Retinoids onPck1 Gene Expression The plasma glucose homeostasis isachieved through its dietary intake and production fromendogenous noncarbohydrate sources During fasting glu-cose is generated via gluconeogenesis The cytosolic form ofphosphoenolpyruvate carboxykinase (PEPCK-C EC41132)which catalyzes the conversion of oxaloacetate into phos-phoenolpyruvate in the presence of GTP [141] has beenconsidered to be the first rate-limiting enzyme of gluconeoge-nesisThe expression of PEPCK-C gene (Pck1) and its activity

have been detected in the liver kidney adipose tissues andsome other tissues [141ndash143] Other than gluconeogenesisPEPCK-C activity has been considered to be responsible forglyceroneogenesis and cataplerosis [144] Since no allostericregulator of PEPCK-C has been identified its activity isprimarily controlled by the level of Pck1mRNA [141ndash143]

The transcription of hepatic Pck1 is regulated by hor-monal and nutritional stimuli In the liver fasting diabetescarbohydrate-free diets and high-fat diets increase Pck1 geneexpression whereas refeeding insulin treatment and high-carbohydrate diets decrease Pck1 gene expression Glucagonglucocorticoids thyroid hormone and RA induce hepaticPck1 expression while insulin and glucose inhibit it [145]

The transcription regulation of Pck1 has been studiedextensively [142 143] The protein-binding sites at the prox-imal region of rat Pck1 promoter have been determined byDNase I footprinting assays [146 147] Multiple regulatoryelements including distal proximal cyclic AMP-responsiveelement (CRE) [148] have been identified Proteins in ratliver nuclear extracts can interact with the two CREs andsix additional binding sites (P1 to 6) [142] The transcrip-tion factors that bind to these sites include HNF4120572 [149]glucocorticoid receptor [148 150ndash153] RAR [154ndash157] TR[154 158] LXR [159] COUP-TF [149] the Forkhead familyof transcription factors [160] CEBP and cAMP regulatoryelement-binding (CREB) protein [161] and SREBP-1c [162163] Additionally transcription coactivators such as CREB-binding protein (CBP) [164] steroid receptor coactivator 1(SRC1) [165] and peroxisome proliferator-activated receptorgamma coactivator-1-alpha (PGC-1120572) [166] also participatein the regulation of hepatic Pck1 gene expression

Using reporter gene assays and hepatoma cells twoRAREs have been identified in the hepatic Pck1 promoter[154 155 167]WhenPEPCKbovine growth hormone (bGH)transgenic mouse strains are used VA deficiency causes thereduction of the transgenersquos transcription [167]The RARE1 isconsidered to be important for mediating the RA-regulatedPck1 expression in the mouse liver [157] In mice VA statusaffects the association of RNApolymerase II and histone codeof Pck1 promoter [168 169] Later on these RAREs have beenshown to bind toHNF4120572 RXR120572 RAR120572 PPAR120572 and COUP-TFII [170]

In an attempt to study the lipophilic molecules that affectinsulin-regulated gene expression in primary rat hepatocyteswe have obtained lipophilic extract (LE) from the rat liverMyoriginal study has shown that this LE induces Pck1 expressionand attenuates insulin-mediated suppression of Pck1 tran-scription in primary rat hepatocytes [171] Interestingly thesame LE synergizes with insulin to induce Gck expression inthe same cells [137]The activemolecules in the LE are retinoland retinal [137] We have shown that retinol retinal andRA all can affect insulin-suppressed Pck1 expression [172]In rat primary hepatocytes the proximal one of the twoRAREs in the rat Pck1 promoter [154ndash156] is responsiblefor mediating the retinoid effects [172] The expression ofhepatic Pck1mRNA in rats seems to respond to VA deficiencydifferently from that in mice We have shown that the hepaticPck1mRNA level in the Zucker lean (ZL) rats is not reduced

8 ISRN Hepatology

Hepatocyte

Induction

Induction

Induction

1 2

Gck

Pck1

Cell membraneCytosol

RA RA

RARESynergy

Signalcascade Insulin

AttenuationNuclear

membrane NucleusRAREs

Inhibitio

n

Figure 2 RA synergizes with insulin to induce Gck expressionand attenuates insulin-suppressed Pck1 expression RA inducesthe expression levels of Gck and Pck1 via the activation of bothRARRXR (the oval dimmers on the RAREs) in the absenceof insulin Insulin alone stimulates the expression of Gck andsuppresses the expression of Pck1 In the presence of both insulinand RA the expression of Gck is further increased (synergy) Onthe other hand the insulin-mediated suppression of Pck1 expressionis attenuated This is because RA still induces Pck1 expressionvia activation of RAR in the presence of insulin Therefore Pck1transcript level in the RA + insulin group is higher than that in theinsulin group (attenuation)

in VA-deficient state [116] VA deficiency only reduces thehepatic Pck1mRNA in the Zucker fatty (ZF) rats [116]

It is important to note that the respective activities of GKand PEPCK-C are induced in different physiological condi-tions For example insulin induces Gck and suppresses Pck1expression as shown in Figure 2 In primary rat hepatocytesactivation of either RARs or RXRs by RA is sufficient toinduce the expression of both Pck1 [172] and Gck [137] How-ever activation of RAR potentiates (for the insulin-mediatedinduction of Gck expression) and attenuates (for the insulin-mediated suppression of Pck1 expression) insulin actionsat the same time in the same hepatocytes For Gck RA-mediated activation of RARs and RXRs can be potentiated byinsulin [137] which results in the synergy For Pck1 only RA-activated RXRs but not RARs are inhibited by insulin whichresults in the attenuation [172] This causes the production ofmore Pck1 mRNA in the presence of RA than in the absenceof it even in the insulin-suppressed state It indicates that themechanisms of RA-mediated activation of RARs and RXRsprobably depend on the promoter context or the isoformsassociated with the promoters of their downstream genesin the presence of insulin Therefore the roles of retinoidsin hepatic glucose metabolism deserve further investigationespecially the roles of the interactions between retinoidsand insulin signaling pathways in the regulation of genetranscription

24 Role of RBP4 in Insulin Resistance Plasma VA is boundto RBP4 which is mainly produced in the liver [13] TheRbp4 mRNA is also expressed to a certain extent in adipose

tissues and kidney [13] In the plasma retinol-RBP4 complexis associated with transthyretin (TTR) a process to increasethe size of the holo-RBP4-TTR complex to reduce the lossduring renal filtration [173]

Recently the plasma RBP4 has been suggested to playroles in metabolic homeostasis It has been reported thatinsulin-resistant human subjects and animals have higherplasma RBP4 levels than normal ones due to its elevatedproduction from adipose tissues [174] In mice RBP4administration has been shown to reduce insulin sensitivityand increase the expression levels of hepatic gluconeogenicgenes such as Pck1 and the catalytic subunit of glucose 6-phosphatase (G6pc) [175] Additionally reduction of plasmaretinol and RBP levels has been reported in type 1 diabeticpatients [176] and in streptozotocin- (STZ-) induced diabeticrats [177] Rbp4 knockout mice have improved insulin sen-sitivity [175] The treatment fenretinide a synthetic retinoidderivative that disrupts the association of RBP4 and TTRimproves insulin sensitivity in HFD-induced obese mice[175]

When a compound specifically developed to disrupt theRBP4 and TTR interaction was used to treat mice it suc-cessfully disrupted the formation of RBP4-TTR complex andcaused the reduction of plasma RBP4 level [178] Howeverthe reduction of plasma RBP4 level did not result in animprovement of insulin sensitivity [178] In addition theimprovement of insulin sensitivity in Rbp4 knockout micecould not be observed in this study [178] Therefore the ele-vation of insulin sensitivity in mice treated with fenretinideis probably due to a mechanism other than the disruption ofRBP-TTR complex and reduction of plasma RBP4 levels

3 Roles of VA in FA and TG Metabolism

FAs are needed for many aspects of cellular functions fromsignal transduction to energy production The continuoussurvival of a given cell depends on the constant energysupplies from the environment or storage sources Thestorage of FA in the form of TG ensures the constant energysupply in a cell or organism for a prolonged period oftime when environment energy is limited In animals thehomeostasis of FA and TG is dynamically regulated by theliver and the adipose tissues in response to nutritional andhormonal stimuli [179 180] During fasting or starvation FAsare released from adipose depots after lipolysis and oxidizedin the liver and muscle for energy production [181] Afterrefeeding dietary and newly synthesized FAs are convertedto TGs for the storage in the adipose tissues [182] On theother hand the altered regulation of this system may causeproblems For example the excessive synthesis and storage ofFAs in the form of TGs can cause the development of obesityand other metabolic diseases

31 The Effects of VA Status on the Body Fat and Plasma LipidProfile VA was first recognized as a dietary lipophilic factorwhich was essential to support the normal growth of labanimals [3 4] Subsequently it was observed that along withthe reduction of body mass the VAD rats that had been fed

ISRN Hepatology 9

aVADdiet at weaning (21 days old) formore than 9weeks hadreduction of carcass fat but not cholesterol content [183] Onthe other hand this reduction of body fat was not observedin the rats of the pair-feeding group which were given thesame amount of a VAS diet in weight and calories as theone consumed by the VAD rats [183] These results indicatethat the reduction of food intake alone could not be used toexplain the depletion of body fat in the VAD rats

The VA status also seems to affect the hepatic expressionof apo AI mRNA The expression of hepatic apo AI hasbeen shown to be sensitive to VA status [184] When theLewis strain rats develop VA deficiency the expression levelof hepatic but not intestinal apo AI mRNA is elevated Thisinduction is dropped upon single dosage of RA treatment[184] On the other hand in the intestine and liver of VA-deficient Wistar rats both all-trans RA and 9-cis RA caninduce apo AI mRNA levels [185] The same treatment canonly induce the mRNA level of apo CIII in the intestine butnot in the liver [185] In humans the plasma VA levels arepositively correlated with the elevations of proteins of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiapatients [186]

When male Wistar rats were fed a VAD diet for 3 monthsafter weaning (21 days old) they had lower plasma TGs andcholesterol levels than the control ones fed a VAS diet [187]When the hepatic synthesis of FAs and phospholipids wasanalyzed in the liver slices the incorporations of [14C]cholineinto phosphatidylcholine and [14C]acetate into FAs were alsoreduced in the VAD rats compared with their VAS controls[187] The VAD rats had lower activities and mRNA levels ofacetyl-CoA carboxylase but higher activity and mRNA levelof carnitine palmitoyltransferase-I than VAS rats had [187]These results demonstrate that there is a reduction of hepaticfatty acid synthesis along with an induction of hepatic fattyacid oxidation in the liver of VAD rats

My lab has conducted experiments and shown that VAstatus affects the obesity development in ZF rats and controlsplasma TG levels in ZL and ZF rats [116] ZF rats a ratmodel of obesity development [188] develop obesity dueto a missense mutation in the extracellular domain of allleptin receptor isoforms [189ndash191] They have been used forthe studies of obesity insulin resistance and other aspectsof metabolic diseases [192 193] We have analyzed growthplasma parameters and expression levels of hepatic genes ofmale ZL and ZF rats fed a VAD or a VAS diet at weaning(21 days of age) for 8 weeks Body masses of ZL and ZF ratsfed the VAD diet are lower than those of their correspondingcontrols fed the VAS diet at the end of the feeding periodThe VAD ZL or ZF rats begin to take less food than the VASones after five weeks on the diet The VAD ZL or ZF rats havelower plasma glucose TG insulin and leptin levels than theircorresponding VAS rats have The liver glycogen content netweights of epididymal fat and liver and fat-to-body massratio (ZL only) in the VAD rats are also lower than those inthe VAS ones [116] This demonstrates that VA status affectsplasma TG levels in both ZF and ZL rats and the obesitydevelopment in ZF rats This phenomenon may be caused by

the combination of VA deficiency and hypoinsulinemia sinceinsulin secretion is impaired in the VAD rats [194]

32 The Development of Hypertriglyceridemia inPatients Receiving Retinoic Acid-Based Treatments

321 The Uses of RA-Based Medicines in Clinic RA-basedmedicines tretinoin (all-trans RA) isotretinoin (13-cis RA)and alitretinoin (9-cis RA) have been used in clinic to treatdiseases such as acute promyelocytic leukemia and skindisorders [11] In fact isotretinoin has been widely used totreat severe acne Early clinical observations indicate that themedical use of isotretinoin in human subjects results in theelevation of their plasma TG levels [195ndash197] A significantportion of patients with acne receiving isotretinoin treatmentdeveloped hypertriglyceridemia [9 10] In addition thesystemic administration of isotretinoin in patients with acneresulted in the elevation of plasma levels of alanine amino-transferase (ALT) and aspartate aminotransferase (AST)indicating the liver damage [198]The hypertriglyceridemia isalso associated with reduced insulin sensitivity and elevatedTG in the very-low-density lipoprotein (VLDL) fraction[195] The treatment of all-trans RA resulted in body massgain and hypertriglyceridemia in patients with acute promye-locytic leukemia [199 200] Moreover RA treatment alsoraises plasma TG levels in rats [201ndash203]

322 The Mechanism of RA-Mediated Hypertriglyceridemiain Patients Apo CIII is produced from liver and consideredan inhibitor of LPL activity [204] Mice with Apoc3 geneknockout have hypotriglyceridemia and enhanced in vivoVLDL-TG clearance [205] On the other hand transgenicmice with overexpression of apo CIII develop hypertriglyc-eridemia [206] The RA-induced hypertriglyceridemia hasbeen attributed to RA-induced apo CIII expression

In healthy human subjects isotretinoin treatment causesa rise of plasma apo CIII protein level [207]This is caused bythe induction of Apoc3 mRNA via the activation of RXR ata RARE in its promoter [207] The plasma TG levels in ratstreated with RXR-specific agonist (LG100268) are inducedrapidly and constantly [208] This results in the reducedactivity of LPL in the heart and skeletal muscle of thoseanimals [208] The RARE is identified in the C3P regionwhich controls the hepatic specific expression of Apoc3 gene[75] Interestingly the same site is also considered to beresponsible for mediating the effects of HNF4120572 and COUP-TFII onApoc3 gene expression [209]The expression ofApoc3seems to be regulated differently by the C3P-binding proteins[75]

It is worth to note that insulin suppresses Apoc3 mRNAexpression in STZ-induced diabetic mice [210] In additionthe activation of RXR by LG100268 treatment induces insulinsensitivity and reduces TG levels in obese and diabetic mice[211] The understanding of the regulatory mechanism thatintegrates hormonal and nutritional signals at the regulatorysites such as C3P in Apoc3 promoter will shed some lightson the regulation of hepatic lipid homeostasis It will also

10 ISRN Hepatology

provide a novel target for the treatment of the RA-inducedhypertriglyeridemia

323 The Effects of RA Treatment on Obesity Developmentin Mice Interestingly the RA administration in rodentscauses reduction of body mass as summarized in [212] Thiskind of reduction of body mass has been associated withenhancement of insulin sensitivity in genetic [213] or DIOmice [108] The mechanisms of RA-mediated attenuation ofinsulin resistance have been thought to be the induction ofenergy expenditure through PPAR120573120575 activation [108] andthe inhibition of adipogenesis throughRXR120574 activation [109]On the other hand retinol can be metabolized in adipose tis-sues [214]Themice with deletion ofRaldh1 gene (Raldh1minusminus)have elevated retinal in their adipose tissues and are resistantto diet-induced obesity and insulin resistance [26] This hasbeen attributed to the suppression of adipogenesis by retinal-inhibited activation of PPAR120574 and RXR [26] It is interestingto note that either retinal or RA can inhibit the adipogenesisand cause the improvement of insulin sensitivity in micebased on these studies

33 Roles of VA and Retinoids in the Regulation of HepaticLipogenic Gene Expression Insulin resistance diabetes andother metabolic abnormalities are associated with profoundchanges of hepatic lipid and glucose metabolismThis can beattributed at least in part to the altered expression of genesinvolved in glucose and lipid metabolism [215] The hepaticlipogenesis contributes to the homeostasis of FAs and TGs

331 The Regulation of Hepatic Srebp-1c Expression by VAStatus and Retinoids Treatment Insulin plays an essentialrole in the hepatic FA synthesis It has been known for a whilethat insulin is needed for the glucose usage for lipogenesis andCO2production in the liver [216] The hepatic FA synthesis

rises sharply and continuously after rats are fasted and thenrefed a high-carbohydrate diet [217] The amount of fattyacid synthase (FAS) is induced in normal rats refed a high-carbohydrate diet after fasting and in STZ-induced diabeticrats after insulin administration [218] In the insulin-deficientrats the induction of FAS after refeeding occurs only wheninsulin injection is injected [219] a process attributed to theinduction of FAS gene (Fas) [220 221]

The transcription of hepatic Fas is controlled by a tran-scription factor named SREBP-1c [222] In the liver-specificSrebp-1c knockoutmouse liver the induction of Fas and otherlipogenic genes by refeeding after fasting is blunted [223]Interestingly insulin also specifically induces the Srebp-1cexpression in the liver [224] via two liver X receptor elements(LXREs) and one sterol-responsive element (SRE) [225]However in liver-specific insulin receptor knockoutmice theinduction of hepatic Srebp-1c by refeeding largely remainedunchanged [226] This suggests that nutrient-derived signalsmay activate downstream of insulin receptor signaling path-way to regulate Srebp-1c expression and hepatic lipogenesis[226]

As stated in the previous section my research group hasobserved that the VAD ZL and ZF rats have lower plasma TG

levels than their VAS controls [116] This is accompanied bythe reduction of the hepatic expression of Srebp-1cmRNA inVA-deficient animals [116] My research group has reportedfor the first time that retinoids synergize with insulin toinduce the expression of Srebp-1c in primary rat hepatocytes[227] Further analysis of the Srebp-1c promoter reveals thatthe previous identified LXREs responsible for mediatinginsulin-induced Srebp-1c expression are also RAREs [227]These observations show that retinoids (nutritional) andinsulin (hormonal) signals converge to regulate the FAsynthesis in the liver

332 The Effects of VA Catabolism on the Regulation of Srebp-1c Expression in Primary Rat Hepatocytes More recentlyretinoids have been proposed to play roles in glucose and lipidmetabolism and to maintain energy homeostasis [228 229]VA (retinol) is reversibly converted into retinal and retinalis irreversibly converted into RA [23] Retinal the precursorof RA production is able to synergize with insulin to inducethe Srebp-1c expression in primary rat hepatocytes [227]This suggests that the dynamic production of RA influencesthe expression of hepatic lipogenic genes It has led us toinvestigate the roles of RA production in the insulin-resistantanimals

In the liver of the Raldh1minusminus mice RA production isreduced in response to a load of retinol [230] The Raldh1minusminusmice are resistant to the development of obesity and insulinresistance after being fed an HFD [26] This is attributed tothe elevation of retinal content due to the lack of conversionof retinal to RA in the adipose tissues of the Raldh1minusminusmice Additionally the liver of the Raldh1minusminus mice hasaltered regulation of the genes for gluconeogenesis andsignificantly attenuated hepatic TG synthesis indicating theimportant role of hepatic VAmetabolism in glucose and lipidhomeostasis [231]

The hepatic expression levels of RALDH1 and RALDH2are induced in mice fed a high-cholesterol diet [232] SREsare located in the promoters of these two genes whichare induced by SREBP-1c overexpression The expression ofSrebp-1c is induced by the oxysterols derived from the high-cholesterol diet [232] This research work demonstrates theinteraction of cholesterol and RA metabolism in the liver Inaddition it has been shown that the level of Raldh1mRNA iselevated in the kidney of dbdb mice [233] Both dbdb miceand ZF rats develop obesity due to the mutation of leptinreceptor [234]

In an attempt to understand the roles of VA metabolismin the states of metabolic diseases we have compared theexpression levels of enzymes responsible for the productionof retinal and RA in the freshly isolated and cultured primaryhepatocytes from ZL rats and ZF rats [45] We have foundthat in the primary rat hepatocytes the enzymes responsiblefor the conversions of retinol to retinal and from retinal toRA are most likely RDH2 and RALDH1 respectively Theexpression levels of Raldh1 mRNA and its protein are higherin hepatocytes from ZF rats than in those from ZL rats[45] When overexpressed RALDH1 introduces the retinal-mediated induction of Srebp-1c in INS-1 cells which do not

ISRN Hepatology 11

respond to retinal in our previous study [227] These resultsindicate that insulin-resistant animals such as ZF rats mayhave alterations in retinoids metabolism

Thus we have hypothesized that the change of RAproduction from the oversupply of dietary VA due to thehyperphagia of ZF rats results in higher Srebp-1c expressionin ZF hepatocytes [45] The elevated SREBP-1c expressioncan further induceRaldh1 expression to create a feed-forwardmechanism that could be one of the reasons responsible forthe increased lipogenesis in the liver of ZF rats All of theseobservations indicate the potential roles of RA metabolismin the development of obesity and insulin resistance whichdeserves to be further studied

4 VArsquos Roles in Mediating Hepatic InsulinAction and Insulin Resistance

41 Insulin and Its Signal Transduction The insulin moleculeis made of two chains linked by one intra- and one interchaindisulfide bonds [235] The insulin receptor is a transmem-brane and heterotetramer tyrosine kinase receptor (two 120572and two 120573 subunits) linked by disulfide bonds as well [236]The binding of insulin to its receptor causes conformationchanges and transphosphorylation of the 120573-subunit tyrosinekinase [237 238] which initiates the signal transduction[239] Protein-protein interactions are involved in the trans-duction of insulin signalThe signal is transduced bymultiplecomponents in a complex network containing cascades ofkinases and phosphatases [240 241] The first intracellularcomponents mediating insulin signals are insulin recep-tor substrates (IRSs) protein molecules phosphorylated byinsulin receptor 120573-subunit and mediating insulin signals[242]

The insulin signal event is further amplified byphosphatidylinositide 3-kinases (PI3K)protein kinaseB (PKBAkt) pathway and GRB2mitogen-activated proteinkinase (MAPK) pathway [243ndash245] Another serinethre-onine kinase that can be activated by PI3K is the atypicalprotein kinase C [246] Human liver expresses severalprotein-tyrosine phosphatases (PTPs) [247] Okadai acid aninhibitor of protein phosphatase type 2A and type 1 inhibitsglycogen synthesis and insulin-stimulated Gck expression inprimary rat hepatocytes indicating that dephosphorylationmechanism may also participate in mediating insulinsignaling [248] These components are shared by insulin-likegrowth factor (IGF) receptor and involved in mediatinginsulin and IGF signals [249]

42 Metabolic Diseases and Insulin Resistance The rise ofthe number of people with one or more metabolic diseasessuch as obesity and diabetes in the world has become apublic health problem [250] The interactions of genetic andenvironmentalnutritional factors may be responsible for thecurrent rise of metabolic diseases The long evolutionaryprocess has equipped human and animal bodieswith a varietyof regulatory mechanisms controlling these interactions [251252] Human diets contain not only energy derived frommacronutrients but also micronutrients and other factors

which may influence the metabolic outcomes The roles ofindividual micronutrients in the development of metabolicdiseases are still unrevealed

One common property of human obesity and NIDDMis insulin resistance in which a given amount of insulinproduces less than normal physiological responses Dietaryfactors and manipulations have been considered to play arole in the development of insulin resistance in humans andanimals For example feeding an HFD to young and insulin-sensitive subjects for two days causes the development ofglucose intolerance [253] In the skeletal muscle of rats fedan HFD for 8 weeks the insulin-induced glucose uptakeis impaired [254] FFAs have been considered the factorsresponsible for HFD-induced leptin and insulin resistance[255ndash257]

43 Hepatic Insulin Resistance and Vicious Cycle The liverplays an essential role in the control of glucose andlipid homeostasis It coordinately regulates the processesin responses to nutritional and hormonal stimuli Insulinplays a major role in directing the liverrsquos metabolic status[258] which is partially attributed to the regulation of theexpression of genes involved in hepatic glucose and lipidmetabolism [215 259]

Insulin controls the expression of a variety of genesinvolved in glycolysis glycogenesis and lipogenesis andgluconeogenesis in the liver [145] Generally hepatic lipidand glucose metabolism is altered with the development ofinsulin resistance in obesity and NIDDM [258] This canbe reflected in the expression of insulin-regulated hepaticgenes for glucose and FA metabolism When the liver isinsulin sensitive insulin stimulates lipogenesis and inhibitsgluconeogenesis For example to regulate hepatic glucosehomeostasis insulin increases the expression of Gck gene[119 120] and Srebp-1c [224] a family member of SREBPswhich regulate the hepatic cholesterol and FA biosynthesisand their homeostasis [260] It suppresses the expressionof Pck1 [142] and G6pc [145] which control the first andlast steps of gluconeogenesis respectively When the liver isinsulin resistant insulin no longer inhibits gluconeogenesisHowever the liver still keeps the elevated lipogenesis Theelevated FA biosynthesis in the insulin-resistant state furtherfacilitates insulin secretion from pancreatic 120573-cells whichprobably enhances lipogenesis and results in a vicious cycle[113 261] The coexistence of the hepatic insulin resistanceand sensitivity at the gene expression level has been observedin rodent obese and diabetic models [215 258] Howeverthe mechanism of this coexistence of insulin sensitivity andresistance has not been revealed [261]

Recently the SREBP cleavage-activating protein gene(Scap) an escort protein necessary for generating nuclearforms of SREBPs has been knocked out in insulin-resistantobob mice [262] Deficiency of hepatic Scap reverses liverlipogenesis and steatosis in obobmice However the plasmalevels of glucose and insulin and the hepatic expression levelsof Pck1 andG6pcwere not different between the control obobmice and the obob mice with liver-specific Scap knockout[262] It seems that the suppression of hepatic FA synthesis

12 ISRN Hepatology

is not sufficient to correct insulin resistance Whether otherfactors play a role in the hepatic insulin resistance is still anopen question

The clinical use of RA-based medicine such asisotretinoin (13-cis RA) caused elevation of plasma TGlevels in human subjects [195ndash197] This increase in plasmaTG levels is also observed in rats [201ndash203] From our VAstatus studies we have shown that VA status affected theobesity development in ZF rats and reduced plasma insulinand TG levels in ZL and ZF rats suggesting improvement ofinsulin sensitivity [116] The hepatic expression of Srebp-1cwas reduced in VA-deficient animals [116] RA synergizeswith insulin to induce the expression of Srebp-1c in primaryrat hepatocytes [227] On the other hand RA treatmentinduces Pck1 expression and attenuates insulin-mediatedsuppression of its expression in primary rat hepatocytes [172]All of these observations demonstrate that RA attenuatesinsulin action (insulin-suppressed Pck1 expression) andstill promotes insulin action (insulin-induced Srebp-1cexpression) in the same primary hepatocytes

44 Possible Mechanism by Which RA Production Causes theDevelopment of the Vicious Cycle in Hepatocytes Could RAor other metabolites from VA catabolism be a factor thatcontributes to the hepatic insulin resistance and the viciouscycleUsing the regulation ofPck1 and Srebp-1c as themodel Ihave come upwith the following scheme to show that retinoidmetabolism could be a factor that causes the vicious cycle inthe liver As shown in Figure 3(a) in insulin-sensitive hepa-tocytes RA derived from retinal coordinates with insulin toregulate the expression of Srebp-1c and Pck1 The SREBP-1cprotein is processed to mature form a step that can be facili-tated by insulin [263] The mature form of SREBP-1c entersinto the nucleus and induces the mRNA levels of Raldh1and Fas which are respectively transcribed into RALDH1and FAS RALDH1 catalyzes the conversion of retinal to RAFAS catalyzes the synthesis of palmitate which is esterifiedinto TGs or elongated to longer FAs The Pck1 mRNA isused to translate into PEPCK-C protein which contributesto glucogenogenesis In the insulin-resistant hepatocytes asshown in Figure 3(b) the elevation of Raldh1 expressiondue to leptin deficiency [45] or induction of SREBP-1c byhigh-cholesterol feeding [232] induces the production of RAThe elevated RA levels will stimulate the transcription ofSrebp-1c and Pck1 This leads to more production of SREBP-1c and its mature form in the presence of higher insulinlevels in the insulin-resistant state The induction of SREBP-1c further enhances the transcription of Raldh1 and Fas andtheir corresponding proteins for the production of moreRAs and FAs respectively The RA production and SREBP-1c expression form a feed-forward cycle which causes moreTG and RA production in the insulin-resistant liver At thesame time more of the PEPCK-C protein is generated dueto the elevated Pck1 transcription by RA stimulation whichis not responsive to insulin inhibition as we have shown in[172] This leads to elevated gluconeogenesis in the insulin-resistant liver Eventually the phenotypes appear as if insulin

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1cRetinal

RALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(a) Insulin-sensitive hepatocytes

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1c

RetinalRALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(b) Insulin-resistant hepatocytes

Figure 3 The effects of RA on the insulin-regulated Srebp-1cand Pck1 expression levels the protein levels of SREBP-1c theexpression levels of Raldh1 and Fas and the fatty acid synthesisand gluconeogenesis in insulin-sensitive (a) and insulin-resistant (b)hepatocytes Please see the text in this paper for description Uparrows next to the text indicate induction The intensified weight ofthe lines indicates the induction of that part of the pathway

no longer suppresses gluconeogenesis while it still stimulatesFA synthesis in the insulin-resistant state

5 Perspectives and Future Directions

I have proposed a mechanism by which VA metabolismcontributes to the development of hepatic insulin resistanceIt explains some observations reported in the previous studiesof rodent obese and diabetic models [215 258] However itleavesmore open questionsThefirst one iswhat the initiationfactor is So far the elevated expression of Raldh1 mRNA inthe liver has been observed in ZF rats [45] and mice fed ahigh-cholesterol diet [232] These two conditions cause a lotof physiological changes such as overfeeding in ZF rats andchange of cholesterol biosynthesis in response to the feedingof high-cholesterol diet Knocking down Raldh1 specificallyin hepatocytes is needed to answer these questions The

ISRN Hepatology 13

second question is whether RA synthesis in hepatocytesis a regulated process in response to dietary or hormonalstimulations If Raldh1 is a downstream gene of SREBP-1cit should be regulated when the SREBP-1c level changes Asthe expression of Srebp-1c responds to insulin stimulation andoxysterols the regulation of Raldh1 expression in the livershould be studied The third question is why it is RALDH1but not other RALDHs Specific inhibitors of RALDHsmay be needed to answer this question Last question iswhether we can attenuate insulin resistance by suppressingthe RALDH1 activity in the liver It has been shown thatRaldh1minusminus mice are still insulin sensitive when they are onan HFD [26] This has been attributed to the effects on theadipogenesis However the liver of those knockout mice hasreduced lipid synthesis [231] Further studies are warrantedto answer all of these questions Hopefully it can become anintervention point for the treatment of insulin resistance andmetabolic diseases

Acknowledgments

This work was financially supported by a research grantfrom Allen Foundation Inc (to Guoxun Chen) a start-up fund from the University of Tennessee at Knoxville (toGuoxun Chen) and a Scientist Development Grant fromthe AmericanHeart Association (09SDG2140003 to GuoxunChen) The author thanks his colleague Dr Lauren Gellar forreading through this paper and offering her edits

References

[1] F G Hopkins ldquoFeeding experiments illustrating the impor-tance of accessory factors in normal dietariesrdquo The Journal ofPhysiology vol 44 no 5-6 pp 425ndash460 1912

[2] K J Carpenter ldquoA short history of nutritional science part 3(1912ndash1944)rdquo Journal of Nutrition vol 133 no 10 pp 3023ndash30322003

[3] E V McCollum and M Davis ldquoThe necessity of certain lipinsin the diet during growthrdquo Journal of Biological Chemistry vol15 no 1 pp 167ndash175 1913

[4] T B Osborne and L B Mendel ldquoFeeding experiments with fat-free food mixturesrdquo Journal of Biological Chemistry vol 12 no1 pp 81ndash89 1912

[5] R D Semba ldquoOn the lsquoDiscoveryrsquo of Vitamin Ardquo Annals ofNutrition and Metabolism vol 61 no 3 pp 192ndash198 2012

[6] R Blomhoff and H K Blomhoff ldquoOverview of retinoidmetabolism and functionrdquo Journal of Neurobiology vol 66 no7 pp 606ndash630 2006

[7] A Sommer ldquoVitamin A deficiency and clinical disease anhistorical overviewrdquo Journal of Nutrition vol 138 no 10 pp1835ndash1839 2008

[8] K J Rothman L L Moore M R Singer U-S Nguyen SMannino and A Milunsky ldquoTeratogenicity of high vitamin Aintakerdquo The New England Journal of Medicine vol 333 no 21pp 1369ndash1373 1995

[9] S Bershad A Rubinstein and J R Paterniti Jr ldquoChanges inplasma lipids and lipoproteins during isotretinoin therapy foracnerdquoThe New England Journal of Medicine vol 313 no 16 pp981ndash985 1985

[10] N Rodondi R Darioli A-A Ramelet et al ldquoHigh risk forhyperlipidemia and the metabolic syndrome after an episodeof hypertriglyceridemia during 13-cis retinoic acid therapy foracne a pharmacogenetic studyrdquo Annals of Internal Medicinevol 136 no 8 pp 582ndash589 2002

[11] H-U Klor A Weizel M Augustin et al ldquoThe impact oforal vitamin A derivatives on lipid metabolism what recom-mendations can be derived for dealing with this issue in thedaily dermatological practicerdquo Journal of the German Societyof Dermatology vol 9 no 8 pp 600ndash607 2011

[12] R M Russell ldquoThe vitamin A spectrum from deficiency totoxicityrdquoThe American Journal of Clinical Nutrition vol 71 no4 pp 878ndash884 2000

[13] A C Ross B Caballero R J Cousins K L Tucker and T RZiegler Modern Nutrition in Health and Diseases 11th edition2012

[14] E H Harrison ldquoMechanisms of digestion and absorption ofdietary vitamin Ardquo Annual Review of Nutrition vol 25 no 1pp 87ndash103 2005

[15] M R Lakshman ldquoAlpha and omega of carotenoid cleavagerdquoJournal of Nutrition vol 134 no 1 pp 241ndash245 2004

[16] I Potrykus ldquoNutritionally enhanced rice to combat malnutri-tion disorders of the poorrdquo Nutrition Reviews vol 61 no 6 ppS101ndashS104 2003

[17] A Wyss ldquoCarotene oxygenases a new family of double bondcleavage enzymesrdquo Journal of Nutrition vol 134 no 1 pp 246ndash250 2004

[18] R Kawaguchi J Yu J Honda et al ldquoA membrane receptor forretinol binding protein mediates cellular uptake of vitamin ArdquoScience vol 315 no 5813 pp 820ndash825 2007

[19] P Alapatt F Guo S M Komanetsky et al ldquoLiver retinoltransporter and receptor for serum retinol-binding protein(RBP4)rdquo Journal of Biological Chemistry vol 288 no 2 pp1250ndash1265 2013

[20] A R Moise N Noy K Palczewski and W S Blaner ldquoDeliveryof retinoid-based therapies to target tissuesrdquo Biochemistry vol46 no 15 pp 4449ndash4458 2007

[21] G Duester ldquoFamilies of retinoid dehydrogenases regulatingvitamin A function Production of visual pigment and retinoicacidrdquo European Journal of Biochemistry vol 267 no 14 pp4315ndash4324 2000

[22] M Theodosiou V Laudet and M Schubert ldquoFrom carrotto clinic an overview of the retinoic acid signaling pathwayrdquoCellular andMolecular Life Sciences vol 67 no 9 pp 1423ndash14452010

[23] J L Napoli ldquoInteractions of retinoid binding proteins andenzymes in retinoidmetabolismrdquoBiochimica et BiophysicaActavol 1440 no 2-3 pp 139ndash162 1999

[24] X Chai M H E M Boerman Y Zhai and J L NapolildquoCloning of a cDNA for liver microsomal retinol dehydro-genase A tissue-specific short-chain alcohol dehydrogenaserdquoJournal of Biological Chemistry vol 270 no 8 pp 3900ndash39041995

[25] B X Wu G Moiseyev Y Chen B Rohrer R K Crouch andJ-XMa ldquoIdentification of RDH10 an all-trans retinol dehydro-genase in retinal Muller cellsrdquo Investigative Ophthalmology andVisual Science vol 45 no 11 pp 3857ndash3862 2004

[26] O Ziouzenkova G Orasanu M Sharlach et al ldquoRetinalde-hyde represses adipogenesis and diet-induced obesityrdquo NatureMedicine vol 13 no 6 pp 695ndash702 2007

14 ISRN Hepatology

[27] J L Napoli ldquoPhysiological insights into all-trans-retinoic acidbiosynthesisrdquo Biochimica et Biophysica Acta vol 1821 no 1 pp152ndash167 2012

[28] G Wolf ldquoTissue-specific increases in endogenous all-transretinoic acid possible contributing factor in ethanol toxicityrdquoNutrition Reviews vol 68 no 11 pp 689ndash692 2010

[29] P V Bhat J Labrecque JM Boutin A Lacroix andA YoshidaldquoCloning of a cDNA encoding rat aldehyde dehydrogenase withhigh activity for retinal oxidationrdquoGene vol 166 no 2 pp 303ndash306 1995

[30] M Lin M Zhang M Abraham S M Smith and J LNapoli ldquoMouse retinal dehydrogenase 4 (RALDH4) molecularcloning cellular expression and activity in 9-cis-retinoic acidbiosynthesis in intact cellsrdquo Journal of Biological Chemistry vol278 no 11 pp 9856ndash9861 2003

[31] F A Mic A Molotkov X Fan A E Cuenca and GDuester ldquoRALDH3 a retinaldehyde dehydrogenase that gener-ates retinoic acid is expressed in the ventral retina otic vesicleand olfactory pit during mouse developmentrdquo Mechanisms ofDevelopment vol 97 no 1-2 pp 227ndash230 2000

[32] X Wang P Penzes and J L Napoli ldquoCloning of a cDNAencoding an aldehyde dehydrogenase and its expression inEscherichia coli recognition of retinal as substraterdquo Journal ofBiological Chemistry vol 271 no 27 pp 16288ndash16293 1996

[33] A Molotkov and G Duester ldquoGenetic evidence that retinalde-hyde dehydrogenase Raldh1 (Aldh1a1) functions downstreamof alcohol dehydrogenase Adh1 in metabolism of retinol toretinoic acidrdquo Journal of Biological Chemistry vol 278 no 38pp 36085ndash36090 2003

[34] G Elizondo J Corchero E Sterneck and F J GonzalezldquoFeedback inhibition of the retinaldehyde dehydrogenase geneALDH1 by retinoic acid through retinoic acid receptor 120572and CCAATenhancer-binding protein 120573rdquo Journal of BiologicalChemistry vol 275 no 50 pp 39747ndash39753 2000

[35] G Elizondo I M Medina-Dıaz R Cruz F J Gonzalez and LVega ldquoRetinoic acid modulates retinaldehyde dehydrogenase 1gene expression through the induction of GADD153-CEBP120573interactionrdquo Biochemical Pharmacology vol 77 no 2 pp 248ndash257 2009

[36] K Fujiwara M Kikuchi K Horiguchi et al ldquoEstrogen receptoralpha regulates retinaldehyde dehydrogenase 1 expression in ratanterior pituitary cellsrdquo Endocrine Journal vol 56 no 8 pp963ndash973 2009

[37] K Fujiwara F Maekawa M Kikuchi S Takigami T Yadaand T Yashiro ldquoExpression of retinaldehyde dehydrogenase(RALDH)2 and RALDH3 but not RALDH1 in the developinganterior pituitary glands of ratsrdquo Cell and Tissue Research vol328 no 1 pp 129ndash135 2007

[38] GWolf ldquoThe enzymatic cleavage of 120573-carotene still controver-sialrdquo Nutrition Reviews vol 53 no 5 pp 134ndash137 1995

[39] S Abu-Abed P Dolle D Metzger B Beckett P Chambonand M Petkovich ldquoThe retinoic acid-metabolizing enzymeCYP26A1 is essential for normal hindbrain patterning verte-bral identity and development of posterior structuresrdquo Genesand Development vol 15 no 2 pp 226ndash240 2001

[40] M A Leo S Iida and C S Lieber ldquoRetinoic acid metabolismby a system reconstituted with cytochrome P-450rdquo Archives ofBiochemistry and Biophysics vol 234 no 1 pp 305ndash312 1984

[41] MA Leo JM Lasker J L Raucy C-I KimM Black andC SLieber ldquoMetabolism of retinol and retinoic acid by human livercytochrome P450IIC8rdquoArchives of Biochemistry and Biophysicsvol 269 no 1 pp 305ndash312 1989

[42] R Quere A Baudet B Cassinat et al ldquoPharmacogenomicanalysis of acute promyelocytic leukemia cells highlightsCYP26cytochrome metabolism in differential all-trans retinoic acidsensitivityrdquo Blood vol 109 no 10 pp 4450ndash4460 2007

[43] J AWhite B Beckett-Jones Y-D Guo et al ldquocDNA cloning ofhuman retinoic acid-metabolizing enzyme (hP450RAI) identi-fies a novel family of cytochromes p450 (CYP26)rdquo Journal ofBiological Chemistry vol 272 no 30 pp 18538ndash18541 1997

[44] Y Zhang R Zolfaghari Reza and A C Ross ldquoMultiple retinoicacid response elements cooperate to enhance the inducibility ofCYP26A1 gene expression in liverrdquo Gene vol 464 no 1-2 pp32ndash43 2010

[45] Y Li Y Zhang R Li et al ldquoThe hepatic raldh1 expression iselevated in Zucker fatty rats and its over-expression introducedthe retinal-induced Srebp-1c expression in INS-1 cellsrdquo PLoSONE vol 7 no 9 Article ID e45210 2012

[46] R M Evans ldquoThe nuclear receptor superfamily a Rosetta stonefor physiologyrdquo Molecular Endocrinology vol 19 no 6 pp1429ndash1438 2005

[47] P Chambon ldquoA decade of molecular biology of retinoic acidreceptorsrdquo FASEB Journal vol 10 no 9 pp 940ndash954 1996

[48] D J Mangelsdorf and RM Evans ldquoThe RXR heterodimers andorphan receptorsrdquo Cell vol 83 no 6 pp 841ndash850 1995

[49] J E Balmer and R Blomhoff ldquoA robust characterization ofretinoic acid response elements based on a comparison of sitesin three speciesrdquo Journal of Steroid Biochemistry and MolecularBiology vol 96 no 5 pp 347ndash354 2005

[50] R Kurokawa J DiRenzo M Boehm et al ldquoRegulation ofretinoid signalling by receptor polarity and allosteric control ofligand bindingrdquo Nature vol 371 no 6497 pp 528ndash531 1994

[51] A Cvekl and W-L Wang ldquoRetinoic acid signaling in mam-malian eye developmentrdquo Experimental Eye Research vol 89no 3 pp 280ndash291 2009

[52] V Dupe M Davenne J Brocard et al ldquoIn vivo functional anal-ysis of the Hoxa-1 31015840 retinoic acid response element (31015840RARE)rdquoDevelopment vol 124 no 2 pp 399ndash410 1997

[53] A C Ross ldquoRetinoid production and catabolism role of dietin regulating retinol esterification and retinoic acid oxidationrdquoJournal of Nutrition vol 133 no 1 pp 291ndash296 2003

[54] T Moore and P D Holmes ldquoThe production of experimentalvitamin A deficiency in rats andmicerdquo Laboratory Animals vol5 no 2 pp 239ndash250 1971

[55] A C Ross and E H Harrison ldquoVitamin A and carotenoidsrdquoin Handbook of Vitamins D E McCormick R R Rucker J WSuttie et al Eds CRC Press Boca Raton Fla USA 4th edition2006

[56] A Chawta J J Repa R M Evans and D J MangelsdorfldquoNuclear receptors and lipid physiology opening the x-filesrdquoScience vol 294 no 5548 pp 1866ndash1870 2001

[57] C K Glass and M G Rosenfeld ldquoThe coregulator exchangein transcriptional functions of nuclear receptorsrdquo Genes andDevelopment vol 14 no 2 pp 121ndash141 2000

[58] A L Bookout Y Jeong M Downes R T Yu R M EvansandD JMangelsdorf ldquoAnatomical profiling of nuclear receptorexpression reveals a hierarchical transcriptional networkrdquo Cellvol 126 no 4 pp 789ndash799 2006

[59] B Mascrez M Mark W Krezel et al ldquoDifferential contribu-tions of AF-1 andAF-2 activities to the developmental functionsof RXR120572rdquo Development vol 128 no 11 pp 2049ndash2062 2001

[60] D Li T Li F Wang H Tian and H H Samuels ldquoFunctionalevidence for retinoid X receptor (RXR) as a nonsilent partner

ISRN Hepatology 15

in the thyroid hormone receptorRXR heterodimerrdquoMolecularand Cellular Biology vol 22 no 16 pp 5782ndash5792 2002

[61] F M Sladek W Zhong E Lai and J E Darnell Jr ldquoLiver-enriched transcription factor HNF-4 is a novel member ofthe steroid hormone receptor superfamilyrdquo Genes and Develop-ment vol 4 no 12 pp 2353ndash2365 1990

[62] K Yamagata H Furuta N Oda et al ldquoMutations in thehepatocyte nuclear factor-4120572 gene inmaturity-onset diabetes ofthe young (MODY1)rdquo Nature vol 384 no 6608 pp 458ndash4601996

[63] M Stoffel and S ADuncan ldquoThematurity-onset diabetes of theyoung (MODY1) transcription factor HNF4120572 regulates expres-sion of genes required for glucose transport and metabolismrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 24 pp 13209ndash13214 1997

[64] M Lehto P-O Bitzen B Isomaa et al ldquoMutation in the HNF-4120572 gene affects insulin secretion and triglyceride metabolismrdquoDiabetes vol 48 no 2 pp 423ndash425 1999

[65] G P Hayhurst Y-H Lee G Lambert J M Ward and F JGonzalez ldquoHepatocyte nuclear factor 4120572 (Nuclear receptor 2A1)is essential formaintenance of hepatic gene expression and lipidhomeostasisrdquo Molecular and Cellular Biology vol 21 no 4 pp1393ndash1403 2001

[66] U Roth K Jungermann and T Kietzmann ldquoActivation ofglucokinase gene expression by hepatic nuclear factor 4120572 inprimary hepatocytesrdquo Biochemical Journal vol 365 no 1 pp223ndash228 2002

[67] S Mandard R Stienstra P Escher et al ldquoGlycogen synthase2 is a novel target gene of peroxisome proliferator-activatedreceptorsrdquo Cellular and Molecular Life Sciences vol 64 no 9pp 1145ndash1157 2007

[68] F Rajas A Gautier I Bady S Montano and G MithieuxldquoPolyunsaturated fatty acyl coenzyme a suppress the glucose-6-phosphatase promoter activity bymodulating the DNA bindingof hepatocyte nuclear factor 4120572rdquo Journal of Biological Chemistryvol 277 no 18 pp 15736ndash15744 2002

[69] B Viollet A Kahn and M Raymondjean ldquoProtein kinase A-dependent phosphorylation modulates DNA-binding activityof hepatocyte nuclear factor 4rdquoMolecular and Cellular Biologyvol 17 no 8 pp 4208ndash4219 1997

[70] L Palanker J M Tennessen G Lam and C S Thum-mel ldquoDrosophila HNF4 regulates lipid mobilization and 120573-oxidationrdquo Cell Metabolism vol 9 no 3 pp 228ndash239 2009

[71] A Miura K Yamagata M Kakei et al ldquoHepatocyte nuclearfactor-4120572 is essential for glucose-stimulated insulin secretion bypancreatic 120573-cellsrdquo Journal of Biological Chemistry vol 281 no8 pp 5246ndash5257 2006

[72] R Bartoov-Shifman R Hertz H Wang C B Wollheim JBar-Tana and M D Walker ldquoActivation of the insulin genepromoter through a direct effect of hepatocyte nuclear factor4120572rdquo Journal of Biological Chemistry vol 277 no 29 pp 25914ndash25919 2002

[73] H Wang P Maechler P A Antinozzi K A Hagenfeldt andC B Wollheim ldquoHepatocyte nuclear factor 4120572 regulates theexpression of pancreatic 120573-cell genes implicated in glucosemetabolism and nutrient-induced insulin secretionrdquo Journal ofBiological Chemistry vol 275 no 46 pp 35953ndash35959 2000

[74] K Reue T Leff and J L Breslow ldquoHuman apolipoproteinCIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factorsrdquo Journal ofBiological Chemistry vol 263 no 14 pp 6857ndash6864 1988

[75] T Leff K Reue A Melian H Culver and J L BreslowldquoA regulatory element in the apoCIII promoter that directshepatic specific transcription binds to proteins in expressingand nonexpressing cell typesrdquo Journal of Biological Chemistryvol 264 no 27 pp 16132ndash16137 1989

[76] S N Lavrentiadou M Hadzopoulou-Cladaras D Kardassisand V I Zannis ldquoBinding specificity and modulation of thehuman apocIII promoter activity by heterodimers of ligand-dependent nuclear receptorsrdquo Biochemistry vol 38 no 3 pp964ndash975 1999

[77] T R Magee Y Cai M E El-Houseini J Locker and Y-JY Wan ldquoRetinoic acid mediates down-regulation of the 120572-fetoprotein gene through decreased expression of hepatocytenuclear factorsrdquo Journal of Biological Chemistry vol 273 no 45pp 30024ndash30032 1998

[78] A Qian Y Cai T R Magee and Y J Y Wan ldquoIdentificationof retinoic acid-responsive elements on the HNF1alpha andHNF4alpha genesrdquo Biochemical and Biophysical Research Com-munications vol 276 no 3 pp 837ndash842 2000

[79] H Nakshatri and P Chambon ldquoThe directly repeatedRG(GT)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites forRAR RXR HNF-4 and ARP-1 homo- and heterodimersrdquoJournal of Biological Chemistry vol 269 no 2 pp 890ndash9021994

[80] T Makita G Hernandez-Hoyos T H-P Chen H Wu E VRothenberg and H M Sucov ldquoA developmental transition indefinitive erythropoiesis erythropoietin expression is sequen-tially regulated by retinoic acid receptors andHNF4rdquoGenes andDevelopment vol 15 no 7 pp 889ndash901 2001

[81] T I Kambe J Tada-Kambe Y Kuge Y Yamaguchi-Iwai MNagao and R Sasaki ldquoRetinoic acid stimulates erythropoietingene transcription in embryonal carcinoma cells through thedirect repeat of a steroidthyroid hormone receptor responseelement half-site in the hypoxia-response enhancerrdquo Blood vol96 no 9 pp 3265ndash3271 2000

[82] F-J Lin J Qin K Tang S Y Tsai and M-J Tsai ldquoCoup drsquoEtatan orphan takes controlrdquo Endocrine Reviews vol 32 no 3 pp404ndash421 2011

[83] L-H Wang S Y Tsai R G Cook W G Beattie M-J Tsaiand BW OrsquoMalley ldquoCOUP transcription factor is a member ofthe steroid receptor superfamilyrdquoNature vol 340 no 6229 pp163ndash166 1989

[84] X Leng A J Cooney S Y Tsai and M-J Tsai ldquoMolecularmechanisms of COUP-TF-mediated transcriptional repressionevidence for transrepression and active repressionrdquo Molecularand Cellular Biology vol 16 no 5 pp 2332ndash2340 1996

[85] L Li X Xie J Qin et al ldquoThe nuclear orphan receptorCOUP-TFII plays an essential role in adipogenesis glucosehomeostasis and energy metabolismrdquo Cell Metabolism vol 9no 1 pp 77ndash87 2009

[86] F A Pereira Q Yuhong G Zhou M-J Tsai and S YTsai ldquoThe orphan nuclear receptor COUP-TFII is required forangiogenesis and heart developmentrdquo Genes and Developmentvol 13 no 8 pp 1037ndash1049 1999

[87] N Takamoto I Kurihara K Lee F J DeMayo M-J Tsai andS Y Tsai ldquoHaploinsufficiency of chicken ovalbumin upstreampromoter transcription factor II in female reproductionrdquoMolec-ular Endocrinology vol 19 no 9 pp 2299ndash2308 2005

[88] P Zhang M Bennoun C Gogard et al ldquoExpression of COUP-TFII in metabolic tissues during developmentrdquo Mechanisms ofDevelopment vol 119 no 1 pp 109ndash114 2002

16 ISRN Hepatology

[89] Z Xu S Yu C-H Hsu J Eguchi and E D Rosen ldquoTheorphan nuclear receptor chicken ovalbumin upstream pro-moter-transcription factor II is a critical regulator of adipogene-sisrdquoProceedings of theNationalAcademy of Sciences of theUnitedStates of America vol 105 no 7 pp 2421ndash2426 2008

[90] P Bardoux P Zhang D Flamez et al ldquoEssential role of chickenovalbumin upstreampromoter-transcription factor II in insulinsecretion and insulin sensitivity revealed by conditional geneknockoutrdquo Diabetes vol 54 no 5 pp 1357ndash1363 2005

[91] G Achatz B Holzl R Speckmayer C Hauser F Sandhoferand B Paulweber ldquoFunctional domains of the human orphanreceptor ARP-1COUP-TFII involved in active repression andtransrepressionrdquo Molecular and Cellular Biology vol 17 no 9pp 4914ndash4932 1997

[92] S A Kliewer K Umesono R A Heyman D J MangelsdorfJ A Dyck and R M Evans ldquoRetinoid X receptor-COUP-TFinteractionsmodulate retinoic acid signalingrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol89 no 4 pp 1448ndash1452 1992

[93] A J Cooney S Y Tsai BW OrsquoMalley andM-J Tsai ldquoChickenovalbumin upstreampromoter transcription factor (COUP-TF)dimers bind to different GGTCA response elements allowingCOUP-TF to repress hormonal induction of the vitamin D3thyroid hormone and retinoic acid receptorsrdquo Molecular andCellular Biology vol 12 no 9 pp 4153ndash4163 1992

[94] SW Kruse K Suino-Powell X E Zhou et al ldquoIdentification ofCOUP-TFII orphannuclear receptor as a retinoic acid-activatedreceptorrdquo PLoS Biology vol 6 no 9 Article ID e227 2008

[95] J P Berger T E Akiyama and P T Meinke ldquoPPARs thera-peutic targets for metabolic diseaserdquo Trends in PharmacologicalSciences vol 26 no 5 pp 244ndash251 2005

[96] JM Peters andF J Gonzalez ldquoSorting out the functional role(s)of peroxisome proliferator-activated receptor-120573120575 (PPAR120573120575)in cell proliferation and cancerrdquo Biochimica et Biophysica Actavol 1796 no 2 pp 230ndash241 2009

[97] A Tenenbaum and E Fisman ldquoBalanced pan-PPAR activatorbezafibrate in combination with statin comprehensive lipidscontrol and diabetes preventionrdquo Cardiovascular Diabetologyvol 11 no 1 article 140 2012

[98] O Braissant F Foufelle C Scotto M Dauca and W WahlildquoDifferential expression of peroxisome proliferator-activatedreceptors (PPARs) tissue distribution of PPAR-120572 -120573 and -120574 inthe adult ratrdquo Endocrinology vol 137 no 1 pp 354ndash366 1996

[99] H Higashiyama A N Billin Y Okamoto M Kinoshita andS Asano ldquoExpression profiling of Peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues usingtissue microarrayrdquo Histochemistry and Cell Biology vol 127 no5 pp 485ndash494 2007

[100] P S Jones R Savory P Barratt et al ldquoChromosomal local-isation inducibility tissue-specific expression and strain dif-ferences in three murine peroxisome-proliferator-activated-receptor genesrdquo European Journal of Biochemistry vol 233 no1 pp 219ndash226 1995

[101] S A Kliewer B M Forman B Blumberg et al ldquoDifferentialexpression and activation of a family of murine peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no15 pp 7355ndash7359 1994

[102] E E Girroir H E Hollingshead P He B Zhu G H Perdewand J M Peters ldquoQuantitative expression patterns of peroxi-some proliferator-activated receptor-120573120575 (PPAR120573120575) protein in

micerdquo Biochemical and Biophysical Research Communicationsvol 371 no 3 pp 456ndash461 2008

[103] P Escher O Braissant S Basu-Modak L Michalik W Wahliand B Desvergne ldquoRat PPARs quantitative analysis in adult rattissues and regulation in fasting and refeedingrdquo Endocrinologyvol 142 no 10 pp 4195ndash4202 2001

[104] D Auboeuf J Rieusset L Fajas et al ldquoTissue distributionand quantification of the expression of mRNAs of peroxi-some proliferator-activated receptors and liver X receptor-120572 inhumans no alteration in adipose tissue of obese and NIDDMpatientsrdquo Diabetes vol 46 no 8 pp 1319ndash1327 1997

[105] N ShawM Elholm andN Noy ldquoRetinoic acid is a high affinityselective ligand for the peroxisome proliferator-activated recep-tor 120573120575rdquo Journal of Biological Chemistry vol 278 no 43 pp41589ndash41592 2003

[106] G Wolf ldquoRetinoic acid as cause of cell proliferation or cellgrowth inhibition depending on activation of one of twodifferent nuclear receptorsrdquoNutrition Reviews vol 66 no 1 pp55ndash59 2008

[107] T T Schug D C Berry N S Shaw S N Travis and N NoyldquoOpposing effects of retinoic acid on cell growth result fromalternate activation of two different nuclear receptorsrdquo Cell vol129 no 4 pp 723ndash733 2007

[108] D C Berry and N Noy ldquoAll-trans-retinoic acid repressesobesity and insulin resistance by activating both peroxisomeproliferation-activated receptor 120573120575 and retinoic acid receptorrdquoMolecular and Cellular Biology vol 29 no 12 pp 3286ndash32962009

[109] D C Berry D DeSantis H Soltanian C M Croniger andN Noy ldquoRetinoic acid upregulates preadipocyte genes to blockadipogenesis and suppress diet-induced obesityrdquo Diabetes vol61 no 5 pp 1112ndash1121 2012

[110] M G Borland C Khozoie P P Albrecht et al ldquoStableover-expression of PPAR120573120575 and PPAR120574 to examine receptorsignaling in human HaCaT keratinocytesrdquo Cellular Signallingvol 23 no 12 pp 2039ndash2050 2011

[111] S E OrsquoSullivan and D A Kendall ldquoCannabinoid activationof peroxisome proliferator-activated receptors potential formodulation of inflammatory diseaserdquo Immunobiology vol 215no 8 pp 611ndash616 2010

[112] Z C Yan D Y Liu L L Zhang et al ldquoExercise reduces adiposetissue via cannabinoid receptor type 1 which is regulated byperoxisome proliferator-activated receptor-120575rdquo Biochemical andBiophysical Research Communications vol 354 no 2 pp 427ndash433 2007

[113] J D McGarry ldquoWhat if Minkowski had been ageusic Analternative angle on diabetesrdquo Science vol 258 no 5083 pp766ndash770 1992

[114] TMoore ldquoVitaminA and carotene the vitaminA reserve of theadult human being in health and diseaserdquo Biochemical Journalvol 31 no 1 pp 155ndash164 1937

[115] GWolfMD Lane and B C Johnson ldquoStudies on the functionof vitamin A in metabolismrdquo Journal of Biological Chemistryvol 225 no 2 pp 995ndash1008 1957

[116] Y Zhang R Li Y Li W Chen S Zhao and G Chen ldquoVitaminA status affects obesity development and hepatic expression ofkey genes for fuel metabolism in Zucker fatty ratsrdquoBiochemistryand Cell Biology vol 90 no 4 pp 548ndash557 2012

[117] M Singh V N Singh and T A Venkitasubramanian ldquoEarlyeffects of feeding excess vitamin A hepatic glycogen bloodlactic acid plasma nefa and glucose tolerance in ratsrdquo LifeSciences vol 7 no 5 pp 239ndash247 1968

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

4 ISRN Hepatology

indicated that RXR was able to bind to ligands and leadto dissociation of corepressors from TR thus modulatingheterodimer activity [60]

143 HNF4120572 for Mediating RA Responses Originally HNF-4120572 (NR2A1 gene Nr2a1) was identified as a transcriptionfactor enriched in liver nuclear extract and was responsiblefor transthyretin gene transcription [61] HNF4120572 is a highlyconserved member of the nuclear receptor superfamilyHNF4120572 binds to DNA as a homodimer and acts as a positivetranscriptional regulator of many hepatic genes Expressionof Nr2a1 gene is driven by two distinct promoters the P1promoter that drives expression of splice variants HNF41205721-6in the liver kidney and intestinecolon and the P2 promoterthat drives expression of splice variants HNF41205727-9 in theintestinecolon stomach and 120573-cells of the pancreas Anonsense mutation (Q268X) in exon 7 of the Nr2a1 genethat caused a deletion of 187 C-terminal amino acids of theHNF4120572 protein was indentified in patients with maturity-onset diabetes of the young type I (MODY1) an autosomaldominant early-onset form of noninsulin-dependent dia-betesmellitus (NIDDM) [62]This shortenedHNF4120572 proteinlacks transcriptional activity and fails to dimerize and bind toDNA [63] Another mutation due to a 2 bp deletion in exon3 of the HNF4120572 gene which results in a truncation of theNr2a1 protein to 122 instead of 465 amino acids causes thecarriers to have significantly lower levels of plasma TG andapolipoprotein CIII (apoCIII) than normal subjects [64]

The roles of HNF4120572 have been studied extensively Liver-specific knockout of HNF4120572 resulted in the reduction ofplasma levels of TG and cholesterol accumulation of hepaticlipid contents and decrease of hepatic expression levels ofapolipoproteins AII AIV CII and CIII [65] Moreover ithas been shown that HNF4120572 can activate the expressionof hepatic glucokinase gene (Gck) after it binds to the Gckpromoter [66]

It seems that there is an interaction of PPAR120572 andHNF4120572signaling pathways In the promoter of mouse glycogensynthase 2 gene (Gys2) there are two putative PPAR responseelements (PPREs) one in the upstream promoter and onein intron 1 [67] The DR1 PPRE in the upstream promoterregion is the response element for HNF4120572 The expressionlevel of Gys2 mRNA in the liver of Nr2a1minusminus mice isdramatically lower than that of the wild-type controls Inaddition the Gys2mRNA level in the liver of Pparaminusminusmiceis also lower than that of the wild-type control mice PPAR120572ligand Wy14643 no longer induces Gys2 mRNA expressionin primary hepatocytes of Pparaminusminus mice In Hep2G cellsPPAR120572 activation significantly reduced HNF4120572-dependenttransactivation of Gys2 promoter demonstrating the interac-tion of their signaling pathways [67]

HNF4120572 although initially believed to be an orphanreceptor activity can be modulated by fatty acyl-coenzyme A(CoA) thioesters [68] and also by protein kinase A-mediatedphosphorylation [69] For drosophila HNF4 (dHNF4) regu-lates lipid mobilization and 120573-oxidation [70] Mutant larvaewith dHnf4 deletionwere unable to efficientlymobilize storedfat for energy during starvation consistent with reduced

expression of genes that control lipid catabolism and 120573-oxidation It seems that FAs released from TGs can activatedHNF4 in fasted drosophila which in turn drives FA oxida-tion for energy production [70] This suggests that HNF4120572may be responsive to dietary signals and important in thecontrol of metabolic status

It has been shown that HNF4120572 is responsible for thefunctions of pancreatic 120573-cells The pancreatic 120573-cell-specificNr2a1minusminus knockout mice have impaired glucose-stimulatedinsulin secretion [71] HNF4120572 activates the insulin geneexpression through indirect and direct mechanisms [72]HNF4120572 also regulates the expression of other pancreatic120573-cell genes involved in glucose metabolism and nutrient-induced insulin secretion including glucose transporter-2and liver-type pyruvate kinase [73]

A relationship between RA signaling pathway andHNF4120572 activation has been indicated in the regulation ofthe hepatic gene expression Multiple sites in the promoterof human apoCIII (APOC3) are responsible for positive andnegative regulation of its transcription in HepG2 cells andthe proximal sequence of a 13-nucleotide element for thepositive regulation of the APOC3 transcription is identicalbetween human and rat genomic sequences [74] It has beenshown that different proteins or forms of the same proteinin the nuclear extract from HepG2 and Hela cells bound tothe same 13-nucleotide sequence element in the promoterof the APOC3 gene [75] The activity of this element is notaffected by its orientation in a reporter construct [75] Theproximal hormone-responsive element B (minus87minus72) bindsstrongly to HNF4 ARP1COUP-TFII EAR2COUP-TFIIIEAR3COUP-TFI and RXR120572RAR120572 heterodimers and lessefficiently to homodimers of RAR120572 and heterodimers ofRXR120572with TR120573 or PPAR120572 [76] InHep3B cells the treatmentof RA caused the reduction ofNr2a1mRNA [77] and HNF4120572protein levels after the RA treatment for 3 days [78]

It was found that RA-mediated downregulation of 120572-fetoprotein gene is dependent on the inhibition of HNF1and HNF4120572 in Hep3B cells [77] Since there is no RARE atthe Nr2a1 gene promoter the mechanism for RA-mediatedinhibition of HNF4120572 remains to be investigated On the otherhandHNF4120572 regulates retinoidmetabolism by activating thetranscription of CRBPII gene [79] Furthermore it has beensuggested that HNF4120572 and RXR120572 compete for occupancyof the same site in erythropoietin gene (Epo) promotersequentially regulating its expression during embryogenesis[80] In the development of mouse embryo the hepaticexpression of erythropoietin is sequentially regulated byRARs and HNF4120572 at days E1025 and E1225 respectively[80] This DR2 RARE is in the 31015840 hypoxia-response enhancerof Epo gene and is responsible for RA-mediated inductionof Epo gene in P19 and F9 embryonal carcinomas but not inHep3B cells [81]

144 COUP-TFII for Mediating RA Responses Chicken oval-bumin upstream promoter-transcription factors (COUP-TFs) are members of a family of evolutionarily con-served orphan nuclear receptor without known physio-logical ligand Currently this family has three members

ISRN Hepatology 5

COUP-TFINR2F1ErbA-related protein-3 (EAR3) COUP-TFIINR2F2apolipoprotein-AI regulatory protein-1 (ARP1)and COUP-TFIIINR2F6 (EAR2) [82] COUP-TFs are con-servative among all species with the ligand-binding domainsof COUP-TFI or -II being identical in vertebrates

The cloning and analysis of COUP-TFII (gene NR2F2)cDNA from Hela cells indicate that it is a member ofnuclear receptor superfamily [83] COUP-TFII seems to berequired earlier in the development processes than COUP-TFI COUP-TFII has been thought to suppress gene expres-sion [84] It has been shown to function in a variety of biolog-ical processes such as development cellular differentiationgrowth and metabolic homeostasis [85] Deletion of Nr2f2in mouse is lethal [82] It has been shown that mice withhomozygous deletion of Nr2f2 die at around E10 probablydue to severe hemorrhage and edema and only one-thirdof the heterozygote mice survive before weaning [86] Nr2f2heterozygous pups have growth retardation in comparisonwith their wild-type controls [87] Adult Nr2f2 heterozygousknockout mice have lower body weight and basal plasmainsulin level but higher insulin sensitivity than that of theirwild-type controls [85] They also exhibit resistance to high-fat diet- (HFD-) induced obesity and improved glucosetolerance [85]

COUP-TFII expression can be detected in a variety ofmetabolic active tissues and organs [88] Since heterozygousmice withNr2f2 deletion have improved glucose homeostasisand increased energy expenditure this indicates that COUP-TFII also plays roles in white adipose tissues developmentand energy metabolism [85] COUP-TFII may suppressadipogenesis via inhibiting the expression of genes foradipocyte differentiation such as the expression of sterolregulatory element-binding protein-1c (SREBP1c) PPAR120574and CCAATenhancer-binding protein 120572 (CEBP120572) [89]COUP-TFII regulates the expression of insulin gene andseveral other genes involved in glucose and lipid metabolismin pancreatic 120573-cells Heterozygous mice with Nr2f2 deletionin pancreatic 120573-cells have impaired glucose sensitivity andabnormal insulin secretion [90]

COUP-TFII regulates gene expression via both protein-protein and protein-DNA interactions [76] For exampleCOUP-TFII binds to hormone response elements (HREs)recognized by other nuclear receptors and in turnmodulatesthe expression of these genes It has been shown that COUP-TFII can bind to a variety of HREs that contain direct orinverted imperfect AGGTCA repeats with various spacesCOUP-TFII can also interact with the common partners orgeneral transcriptional factors to modulate gene expression[84 91] For example the amount of RXR available for theformation of high-affinity DNA-binding complexes of thethyroid hormoneRAR subfamily can be limited COUP-TFIIcan also actively silence basal and activated transcriptionlikely through direct interaction with TFIIB or other generaltranscription factors [84]Therefore COUP-TFII may antag-onize the functions of other hormones and in turn alter thecellular responses to multiple-hormone signaling pathwaysand it can have profound effects on metabolic homeostasis

COUP-TF protein interacts with RXR120572 to form het-erodimer [92] Using RXR120572 cDNA probe COUP-TFs were

identified to bind to RAREs The original COUP-TF-bindingsite in the ovalbumin gene is also a RARE that is repressedby COUP-TF [93] On the other hand RXR120572 and COUP-TFII can bind to the same DR1 element individually or inthe heterodimeric form in an electrophoresis mobility shiftassay (EMSA) Cotransfection of COUP-TFII and RXR120572suppresses RXR-mediated activation of CRBPII promoterwhich contains one RARE [92] COUP-TFs are involved inthe modulation of RAR- and RXR-mediated responses toretinoids during embryogenesis [84] Recently COUP-TFIIhas been identified as a low-affinity RA receptor The ligandbinding of COUP-TFII is in an autorepressed conformationAt high concentrations RA is able to promote COUP-TFIIto recruit coactivators and to activate a COUP-TF reporterconstruct [94] These observations suggest a linkage betweenRA and COUP-TFII signaling pathways

145 PPAR120573120575 forMediating RAResponses PPARs aremem-bers of nuclear receptor superfamily They take part in theregulation of a variety of physiological functions such as celldifferentiation metabolism and immune functions [95] Sofar three PPAR isoforms PPAR120572 PPAR120573120575 and PPAR120574are identified and reported The expression of PPAR120573120575 isubiquitous which can be detected in a lot of cell typesand tissues [96 97] In rats PPAR120573120575 mRNA and proteinsare expressed ubiquitously and often coexpressed with otherPPARs [98] Similar expression profiles are observed inmice [99ndash101] In mice PPAR120573120575 protein can be detectedin a variety of tissues with high expression levels in thesmall intestine skin and liver [102] The expression levels ofPPAR120573120575mRNA and protein in the liver of rats fasted for 12hours are reduced and increased upon refeeding for 45 hours[103]The expression of low levels of human PPAR120573120575mRNAcan be detected in the adipose tissues the skeletal muscle theliver the kidney and the intestines [104]

It has been shown that RA is a high-affinity ligand(nanomolar range) for PPAR120573120575 activation in COS-7 cells[105] RA-mediated activation of PPAR120573120575 plays a role incell proliferation [106] In certain types of cells RA isrespectively delivered to RAR and PPAR120573120575 by cytosolretinoic acid-binding protein II (CRABP-II) and fatty acid-binding protein 5 [107] The activation of these two receptorsby RA has opposite effects on cell growth RA can activatePPAR120573120575 in preadipocytes and mature adipocytes [108 109]RA treatment prevents obesity development in diet-inducedobesity (DIO) via increase of lipolysis [108] and inhibition ofadipocyte differentiation [109]

However when human PPAR120573120575 was stably over-expressed in human keratinocyte cells no change inPPAR120573120575 target gene expression could be observed after thetreatment of RA [110] Many studies have shown that endo-cannabinoids regulate the activity of PPARs via direct andindirect mechanisms [111] The expression of endocannabi-noid receptor type 1 (CB1) is reduced upon overexpressionof PPAR120573120575 suggesting other pathways that PPAR120573120575 isinvolved in [112]

In summary retinol in hepatocytes can be either storedas REs or oxidized into retinal as shown in Figure 1 RA

6 ISRN Hepatology

HepatocyteCell membrane

RE Retinol Retinal RA

Other metabolic pathwaysNuclear

membrane

Cytosol RAOther ligands

RARRXR PPAR120573120575

COUP-TFII UpdownmRNAHNF4120572HNF4120572

RARE

Nucleus

Figure 1 The effects of RA production and other metabolicfactors on the activities of transcription factors associated with aretinoic acid-responsive element (RARE) in the promoter of anRA-targeted gene In primary hepatocytes RA is produced fromretinal derived from retinol Retinol can be esterified into retinylester (RE) or oxidized into retinal The RARE can be occupied byretinoic acid receptor (RAR) retinoid X receptor (RXR) hepatocytenuclear factor 4120572 (HNF4120572) chicken ovalbumin upstreampromoter-transcription factor II (COUP-TFII) and peroxisome proliferator-activated receptor 120573120575 (PPAR120573120575) in the forms of heterodimers orhomodimers These transcription factors receive signals from RAand metabolic pathways and regulate the expression of the RA-responsive gene

is dynamically produced and sent to nucleus where itinteracts with transcription factors associated with RAREin the enhancer regions of the RA-responsive genes Sofar the transcription factors that can be associated with aparticular RARE include RAR RXR COUP-TFII HNF4120572and PPAR120573120575 They form heterodimers or homodimers andbind to RARE to regulate the transcription rate of that geneThe nuclear receptors that occupy the RARE at any givenmoment may be determined by the VA status of the animaland the developmental differentiation and metabolic statesof hepatocytes These transcription factors integrate signalsfrom RA and other metabolic pathways to control the geneexpression positively and negatively Other metabolic signalsin combination with RA may affect the occupancy of thenuclear receptors bound to the RARE and their activationsand may in turn alter the outcomes of the RA-mediatedtranscription responses

2 VArsquos Roles in Glucose Metabolism

As a convenient energy source glucose can be used by all cellsthat are in charge of different physiological functionsGlucoseis metabolized differently in response to hormonal and nutri-tional statuses [113] Hepatocytes utilize and produce glucosedepending on the physiological needs and feeding status ofa subject These processes are regulated by nutritional andhormonal stimuli VA status has been implied to play a role

21 The Effects of VA Status on Hepatic Glycogen ContentsThe roles of VA in glucose metabolism had been suggestedIn 1937 the liver samples of patients who died of diabetesshowed an elevation of VA contents [114] When rats werefed a VA-deficient (VAD) diet to induce VA deficiency theirliver glycogen content was depleted [115] Since VA deficiencyalso caused reduction of food intake in the VAD rats a pair-feeding control group was included The pair-fed rats withequal energy intake as that of VAD rats had higher hepaticglycogen content [115] This depletion of hepatic glycogencontent was attributed to the reduction of glycogenesisfrom trioses rather than directly from glucose [115] Thephenomenon of the depletion of hepatic glycogen contentin the liver of VAD rats has also been observed recently inmy lab [116] On the other hand when rats were fed a dietwith excessive amounts of VA for two days an elevation ofthe hepatic glycogen content in the liver after fasting wasobserved [117] It seems that hepatic VA content is directlycorrelated with the hepatic glycogen content

22 The Effects of Animal VA Statuses and Retinoids onHepatic Gck Expression To initiate the hepatic glucose uti-lization glucose is phosphorylated into glucose 6-phosphateby hexokinases in the first reaction of glycolysis So far fourhexokinase isozymes hexokinase I (A) II (B) III (C) andIV (D) have been identified They have different tissue dis-tributions intracellular locations and kinetic characteristicsMammalian hexokinase IV (D) is also known as glucokinase(GK) (ATP d-hexose 6-phosphotransferase EC 2711) [118ndash121] Mutations of GK have been associated with MODY[122] GK has two unique features that differentiate it fromother hexokinase family members It has low affinity forglucose (higher Km) and it is insensitive to allosteric inhi-bition mediated by physiological concentrations of glucose6-phosphate whereas other hexokinases are sensitive to it[118 121 123 124] In addition to glucose other substrates ofGK include fructose mannose and 2-deoxyglucose [118]

Generally GK activity is mainly observed in the liverand pancreatic islets The 120573-cells and liver GK isoforms havesimilar kinetic properties [125 126] In the short term theGK activity can be regulated via allosteric interactions andcovalent modifications such as binding to GK regulatoryprotein [127] phosphorylation by protein kinase A [128] andinteractionwith a cytosolic GK-associated phosphatase [129]

The long-term regulation of GK activity is done throughthe transcription of its gene Gck which is differentiallyregulated by an upstream promoter in pancreatic 120573-cells anda downstream promoter in hepatocytes [130 131] Using astrain of transgenic mice containing the cDNA of humangrowth hormone gene driven by an upstream Gck promoterfragmentGck expression has been found in certain neuroen-docrine cells of the pancreas pituitary brain gut thyroidand lungs [132] Activation of the upstream or downstreampromoter leads to the generation of a Gck mRNA with aunique 51015840 sequence derived from exon 1120573 or 1L respectivelySince the translation initiation coden is located in the firstexon the GK proteins encoded by the different transcriptsdiffer in the first 15 amino acids at the amino terminus

ISRN Hepatology 7

[130 131] The mechanisms by which the upstream and thedownstream promoters are selectively activated in differentcells have not been revealedThe temporal and special controlof the promoter selectionmust be determined by signals fromdifferentiation and development processes

The upstream and downstream promoters are activatedbased on the hormonal and nutritional conditions of thesubject For example the hepatic but not the pancreatic 120573-cell Gck expression is reduced while fasting and increasedwhile refeeding [130] In the rat liver insulin and glucagonrespectively induce and inhibit the expression of GckmRNA[133ndash135] A long-standing question in the field is the insulin-responsive element (IRE) responsible for the insulin-inducedhepaticGck expression Using the reporter gene constructs tostudy insulin-induced Gck promoter activation has not beensuccessful For example a reporter gene construct containinga fragment of 55 kb hepatic Gck promoter failed to showany response to insulin treatment in rat primary hepatocytes[136] This suggests that the IRE of the hepatic Gck mightbe in an area not included in this 55 kb promoter fragmentAlternatively the unresponsiveness to insulin of the reportergene constructs in the experimental settings could be due tothe short-lived signal from insulin for Gck transcription aswe have shownpreviously [137] Interestingly the hepatocyte-specific enhancer region that controls the activation of liver-specific promoter has been located in the region from minus1003to minus707 relative to the transcription initiation site in primaryrat hepatocytes By contrast this region acts as a silencer inFTO-2B hepatoma cells and has no effects on insulinomacells [138] Further studies are needed to identify the insulin-responsive element in the hepatic Gck promoter

The direct effects of RA on the expression of Gck mRNAin primary rat hepatocytes have been studied Previouslyothers have shown that all-trans RA induced Gck expressionin primary rat hepatocytes However nonadditive effect ofRA on insulin-induced Gck expression was observed [139140] Recently we have shown that retinoids synergized withinsulin to induce Gck expression in primary rat hepatocytes[137] We have observed that all-trans retinol retinal and RAare able to synergize with insulin to induce Gck expressionprobably via the activation of RARRXR in primary rat hepa-tocytes In addition VA status also controls the expression ofhepatic Gck expression [137] The levels of Gck mRNA [116]and its activity [137] in the liver of VAD rats are lower thanthose of VA-sufficient (VAS) controls In addition a singletreatment of RA increases the hepatic Gck expression in rats[137]

23 The Effects of Animal VA Status and Retinoids onPck1 Gene Expression The plasma glucose homeostasis isachieved through its dietary intake and production fromendogenous noncarbohydrate sources During fasting glu-cose is generated via gluconeogenesis The cytosolic form ofphosphoenolpyruvate carboxykinase (PEPCK-C EC41132)which catalyzes the conversion of oxaloacetate into phos-phoenolpyruvate in the presence of GTP [141] has beenconsidered to be the first rate-limiting enzyme of gluconeoge-nesisThe expression of PEPCK-C gene (Pck1) and its activity

have been detected in the liver kidney adipose tissues andsome other tissues [141ndash143] Other than gluconeogenesisPEPCK-C activity has been considered to be responsible forglyceroneogenesis and cataplerosis [144] Since no allostericregulator of PEPCK-C has been identified its activity isprimarily controlled by the level of Pck1mRNA [141ndash143]

The transcription of hepatic Pck1 is regulated by hor-monal and nutritional stimuli In the liver fasting diabetescarbohydrate-free diets and high-fat diets increase Pck1 geneexpression whereas refeeding insulin treatment and high-carbohydrate diets decrease Pck1 gene expression Glucagonglucocorticoids thyroid hormone and RA induce hepaticPck1 expression while insulin and glucose inhibit it [145]

The transcription regulation of Pck1 has been studiedextensively [142 143] The protein-binding sites at the prox-imal region of rat Pck1 promoter have been determined byDNase I footprinting assays [146 147] Multiple regulatoryelements including distal proximal cyclic AMP-responsiveelement (CRE) [148] have been identified Proteins in ratliver nuclear extracts can interact with the two CREs andsix additional binding sites (P1 to 6) [142] The transcrip-tion factors that bind to these sites include HNF4120572 [149]glucocorticoid receptor [148 150ndash153] RAR [154ndash157] TR[154 158] LXR [159] COUP-TF [149] the Forkhead familyof transcription factors [160] CEBP and cAMP regulatoryelement-binding (CREB) protein [161] and SREBP-1c [162163] Additionally transcription coactivators such as CREB-binding protein (CBP) [164] steroid receptor coactivator 1(SRC1) [165] and peroxisome proliferator-activated receptorgamma coactivator-1-alpha (PGC-1120572) [166] also participatein the regulation of hepatic Pck1 gene expression

Using reporter gene assays and hepatoma cells twoRAREs have been identified in the hepatic Pck1 promoter[154 155 167]WhenPEPCKbovine growth hormone (bGH)transgenic mouse strains are used VA deficiency causes thereduction of the transgenersquos transcription [167]The RARE1 isconsidered to be important for mediating the RA-regulatedPck1 expression in the mouse liver [157] In mice VA statusaffects the association of RNApolymerase II and histone codeof Pck1 promoter [168 169] Later on these RAREs have beenshown to bind toHNF4120572 RXR120572 RAR120572 PPAR120572 and COUP-TFII [170]

In an attempt to study the lipophilic molecules that affectinsulin-regulated gene expression in primary rat hepatocyteswe have obtained lipophilic extract (LE) from the rat liverMyoriginal study has shown that this LE induces Pck1 expressionand attenuates insulin-mediated suppression of Pck1 tran-scription in primary rat hepatocytes [171] Interestingly thesame LE synergizes with insulin to induce Gck expression inthe same cells [137]The activemolecules in the LE are retinoland retinal [137] We have shown that retinol retinal andRA all can affect insulin-suppressed Pck1 expression [172]In rat primary hepatocytes the proximal one of the twoRAREs in the rat Pck1 promoter [154ndash156] is responsiblefor mediating the retinoid effects [172] The expression ofhepatic Pck1mRNA in rats seems to respond to VA deficiencydifferently from that in mice We have shown that the hepaticPck1mRNA level in the Zucker lean (ZL) rats is not reduced

8 ISRN Hepatology

Hepatocyte

Induction

Induction

Induction

1 2

Gck

Pck1

Cell membraneCytosol

RA RA

RARESynergy

Signalcascade Insulin

AttenuationNuclear

membrane NucleusRAREs

Inhibitio

n

Figure 2 RA synergizes with insulin to induce Gck expressionand attenuates insulin-suppressed Pck1 expression RA inducesthe expression levels of Gck and Pck1 via the activation of bothRARRXR (the oval dimmers on the RAREs) in the absenceof insulin Insulin alone stimulates the expression of Gck andsuppresses the expression of Pck1 In the presence of both insulinand RA the expression of Gck is further increased (synergy) Onthe other hand the insulin-mediated suppression of Pck1 expressionis attenuated This is because RA still induces Pck1 expressionvia activation of RAR in the presence of insulin Therefore Pck1transcript level in the RA + insulin group is higher than that in theinsulin group (attenuation)

in VA-deficient state [116] VA deficiency only reduces thehepatic Pck1mRNA in the Zucker fatty (ZF) rats [116]

It is important to note that the respective activities of GKand PEPCK-C are induced in different physiological condi-tions For example insulin induces Gck and suppresses Pck1expression as shown in Figure 2 In primary rat hepatocytesactivation of either RARs or RXRs by RA is sufficient toinduce the expression of both Pck1 [172] and Gck [137] How-ever activation of RAR potentiates (for the insulin-mediatedinduction of Gck expression) and attenuates (for the insulin-mediated suppression of Pck1 expression) insulin actionsat the same time in the same hepatocytes For Gck RA-mediated activation of RARs and RXRs can be potentiated byinsulin [137] which results in the synergy For Pck1 only RA-activated RXRs but not RARs are inhibited by insulin whichresults in the attenuation [172] This causes the production ofmore Pck1 mRNA in the presence of RA than in the absenceof it even in the insulin-suppressed state It indicates that themechanisms of RA-mediated activation of RARs and RXRsprobably depend on the promoter context or the isoformsassociated with the promoters of their downstream genesin the presence of insulin Therefore the roles of retinoidsin hepatic glucose metabolism deserve further investigationespecially the roles of the interactions between retinoidsand insulin signaling pathways in the regulation of genetranscription

24 Role of RBP4 in Insulin Resistance Plasma VA is boundto RBP4 which is mainly produced in the liver [13] TheRbp4 mRNA is also expressed to a certain extent in adipose

tissues and kidney [13] In the plasma retinol-RBP4 complexis associated with transthyretin (TTR) a process to increasethe size of the holo-RBP4-TTR complex to reduce the lossduring renal filtration [173]

Recently the plasma RBP4 has been suggested to playroles in metabolic homeostasis It has been reported thatinsulin-resistant human subjects and animals have higherplasma RBP4 levels than normal ones due to its elevatedproduction from adipose tissues [174] In mice RBP4administration has been shown to reduce insulin sensitivityand increase the expression levels of hepatic gluconeogenicgenes such as Pck1 and the catalytic subunit of glucose 6-phosphatase (G6pc) [175] Additionally reduction of plasmaretinol and RBP levels has been reported in type 1 diabeticpatients [176] and in streptozotocin- (STZ-) induced diabeticrats [177] Rbp4 knockout mice have improved insulin sen-sitivity [175] The treatment fenretinide a synthetic retinoidderivative that disrupts the association of RBP4 and TTRimproves insulin sensitivity in HFD-induced obese mice[175]

When a compound specifically developed to disrupt theRBP4 and TTR interaction was used to treat mice it suc-cessfully disrupted the formation of RBP4-TTR complex andcaused the reduction of plasma RBP4 level [178] Howeverthe reduction of plasma RBP4 level did not result in animprovement of insulin sensitivity [178] In addition theimprovement of insulin sensitivity in Rbp4 knockout micecould not be observed in this study [178] Therefore the ele-vation of insulin sensitivity in mice treated with fenretinideis probably due to a mechanism other than the disruption ofRBP-TTR complex and reduction of plasma RBP4 levels

3 Roles of VA in FA and TG Metabolism

FAs are needed for many aspects of cellular functions fromsignal transduction to energy production The continuoussurvival of a given cell depends on the constant energysupplies from the environment or storage sources Thestorage of FA in the form of TG ensures the constant energysupply in a cell or organism for a prolonged period oftime when environment energy is limited In animals thehomeostasis of FA and TG is dynamically regulated by theliver and the adipose tissues in response to nutritional andhormonal stimuli [179 180] During fasting or starvation FAsare released from adipose depots after lipolysis and oxidizedin the liver and muscle for energy production [181] Afterrefeeding dietary and newly synthesized FAs are convertedto TGs for the storage in the adipose tissues [182] On theother hand the altered regulation of this system may causeproblems For example the excessive synthesis and storage ofFAs in the form of TGs can cause the development of obesityand other metabolic diseases

31 The Effects of VA Status on the Body Fat and Plasma LipidProfile VA was first recognized as a dietary lipophilic factorwhich was essential to support the normal growth of labanimals [3 4] Subsequently it was observed that along withthe reduction of body mass the VAD rats that had been fed

ISRN Hepatology 9

aVADdiet at weaning (21 days old) formore than 9weeks hadreduction of carcass fat but not cholesterol content [183] Onthe other hand this reduction of body fat was not observedin the rats of the pair-feeding group which were given thesame amount of a VAS diet in weight and calories as theone consumed by the VAD rats [183] These results indicatethat the reduction of food intake alone could not be used toexplain the depletion of body fat in the VAD rats

The VA status also seems to affect the hepatic expressionof apo AI mRNA The expression of hepatic apo AI hasbeen shown to be sensitive to VA status [184] When theLewis strain rats develop VA deficiency the expression levelof hepatic but not intestinal apo AI mRNA is elevated Thisinduction is dropped upon single dosage of RA treatment[184] On the other hand in the intestine and liver of VA-deficient Wistar rats both all-trans RA and 9-cis RA caninduce apo AI mRNA levels [185] The same treatment canonly induce the mRNA level of apo CIII in the intestine butnot in the liver [185] In humans the plasma VA levels arepositively correlated with the elevations of proteins of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiapatients [186]

When male Wistar rats were fed a VAD diet for 3 monthsafter weaning (21 days old) they had lower plasma TGs andcholesterol levels than the control ones fed a VAS diet [187]When the hepatic synthesis of FAs and phospholipids wasanalyzed in the liver slices the incorporations of [14C]cholineinto phosphatidylcholine and [14C]acetate into FAs were alsoreduced in the VAD rats compared with their VAS controls[187] The VAD rats had lower activities and mRNA levels ofacetyl-CoA carboxylase but higher activity and mRNA levelof carnitine palmitoyltransferase-I than VAS rats had [187]These results demonstrate that there is a reduction of hepaticfatty acid synthesis along with an induction of hepatic fattyacid oxidation in the liver of VAD rats

My lab has conducted experiments and shown that VAstatus affects the obesity development in ZF rats and controlsplasma TG levels in ZL and ZF rats [116] ZF rats a ratmodel of obesity development [188] develop obesity dueto a missense mutation in the extracellular domain of allleptin receptor isoforms [189ndash191] They have been used forthe studies of obesity insulin resistance and other aspectsof metabolic diseases [192 193] We have analyzed growthplasma parameters and expression levels of hepatic genes ofmale ZL and ZF rats fed a VAD or a VAS diet at weaning(21 days of age) for 8 weeks Body masses of ZL and ZF ratsfed the VAD diet are lower than those of their correspondingcontrols fed the VAS diet at the end of the feeding periodThe VAD ZL or ZF rats begin to take less food than the VASones after five weeks on the diet The VAD ZL or ZF rats havelower plasma glucose TG insulin and leptin levels than theircorresponding VAS rats have The liver glycogen content netweights of epididymal fat and liver and fat-to-body massratio (ZL only) in the VAD rats are also lower than those inthe VAS ones [116] This demonstrates that VA status affectsplasma TG levels in both ZF and ZL rats and the obesitydevelopment in ZF rats This phenomenon may be caused by

the combination of VA deficiency and hypoinsulinemia sinceinsulin secretion is impaired in the VAD rats [194]

32 The Development of Hypertriglyceridemia inPatients Receiving Retinoic Acid-Based Treatments

321 The Uses of RA-Based Medicines in Clinic RA-basedmedicines tretinoin (all-trans RA) isotretinoin (13-cis RA)and alitretinoin (9-cis RA) have been used in clinic to treatdiseases such as acute promyelocytic leukemia and skindisorders [11] In fact isotretinoin has been widely used totreat severe acne Early clinical observations indicate that themedical use of isotretinoin in human subjects results in theelevation of their plasma TG levels [195ndash197] A significantportion of patients with acne receiving isotretinoin treatmentdeveloped hypertriglyceridemia [9 10] In addition thesystemic administration of isotretinoin in patients with acneresulted in the elevation of plasma levels of alanine amino-transferase (ALT) and aspartate aminotransferase (AST)indicating the liver damage [198]The hypertriglyceridemia isalso associated with reduced insulin sensitivity and elevatedTG in the very-low-density lipoprotein (VLDL) fraction[195] The treatment of all-trans RA resulted in body massgain and hypertriglyceridemia in patients with acute promye-locytic leukemia [199 200] Moreover RA treatment alsoraises plasma TG levels in rats [201ndash203]

322 The Mechanism of RA-Mediated Hypertriglyceridemiain Patients Apo CIII is produced from liver and consideredan inhibitor of LPL activity [204] Mice with Apoc3 geneknockout have hypotriglyceridemia and enhanced in vivoVLDL-TG clearance [205] On the other hand transgenicmice with overexpression of apo CIII develop hypertriglyc-eridemia [206] The RA-induced hypertriglyceridemia hasbeen attributed to RA-induced apo CIII expression

In healthy human subjects isotretinoin treatment causesa rise of plasma apo CIII protein level [207]This is caused bythe induction of Apoc3 mRNA via the activation of RXR ata RARE in its promoter [207] The plasma TG levels in ratstreated with RXR-specific agonist (LG100268) are inducedrapidly and constantly [208] This results in the reducedactivity of LPL in the heart and skeletal muscle of thoseanimals [208] The RARE is identified in the C3P regionwhich controls the hepatic specific expression of Apoc3 gene[75] Interestingly the same site is also considered to beresponsible for mediating the effects of HNF4120572 and COUP-TFII onApoc3 gene expression [209]The expression ofApoc3seems to be regulated differently by the C3P-binding proteins[75]

It is worth to note that insulin suppresses Apoc3 mRNAexpression in STZ-induced diabetic mice [210] In additionthe activation of RXR by LG100268 treatment induces insulinsensitivity and reduces TG levels in obese and diabetic mice[211] The understanding of the regulatory mechanism thatintegrates hormonal and nutritional signals at the regulatorysites such as C3P in Apoc3 promoter will shed some lightson the regulation of hepatic lipid homeostasis It will also

10 ISRN Hepatology

provide a novel target for the treatment of the RA-inducedhypertriglyeridemia

323 The Effects of RA Treatment on Obesity Developmentin Mice Interestingly the RA administration in rodentscauses reduction of body mass as summarized in [212] Thiskind of reduction of body mass has been associated withenhancement of insulin sensitivity in genetic [213] or DIOmice [108] The mechanisms of RA-mediated attenuation ofinsulin resistance have been thought to be the induction ofenergy expenditure through PPAR120573120575 activation [108] andthe inhibition of adipogenesis throughRXR120574 activation [109]On the other hand retinol can be metabolized in adipose tis-sues [214]Themice with deletion ofRaldh1 gene (Raldh1minusminus)have elevated retinal in their adipose tissues and are resistantto diet-induced obesity and insulin resistance [26] This hasbeen attributed to the suppression of adipogenesis by retinal-inhibited activation of PPAR120574 and RXR [26] It is interestingto note that either retinal or RA can inhibit the adipogenesisand cause the improvement of insulin sensitivity in micebased on these studies

33 Roles of VA and Retinoids in the Regulation of HepaticLipogenic Gene Expression Insulin resistance diabetes andother metabolic abnormalities are associated with profoundchanges of hepatic lipid and glucose metabolismThis can beattributed at least in part to the altered expression of genesinvolved in glucose and lipid metabolism [215] The hepaticlipogenesis contributes to the homeostasis of FAs and TGs

331 The Regulation of Hepatic Srebp-1c Expression by VAStatus and Retinoids Treatment Insulin plays an essentialrole in the hepatic FA synthesis It has been known for a whilethat insulin is needed for the glucose usage for lipogenesis andCO2production in the liver [216] The hepatic FA synthesis

rises sharply and continuously after rats are fasted and thenrefed a high-carbohydrate diet [217] The amount of fattyacid synthase (FAS) is induced in normal rats refed a high-carbohydrate diet after fasting and in STZ-induced diabeticrats after insulin administration [218] In the insulin-deficientrats the induction of FAS after refeeding occurs only wheninsulin injection is injected [219] a process attributed to theinduction of FAS gene (Fas) [220 221]

The transcription of hepatic Fas is controlled by a tran-scription factor named SREBP-1c [222] In the liver-specificSrebp-1c knockoutmouse liver the induction of Fas and otherlipogenic genes by refeeding after fasting is blunted [223]Interestingly insulin also specifically induces the Srebp-1cexpression in the liver [224] via two liver X receptor elements(LXREs) and one sterol-responsive element (SRE) [225]However in liver-specific insulin receptor knockoutmice theinduction of hepatic Srebp-1c by refeeding largely remainedunchanged [226] This suggests that nutrient-derived signalsmay activate downstream of insulin receptor signaling path-way to regulate Srebp-1c expression and hepatic lipogenesis[226]

As stated in the previous section my research group hasobserved that the VAD ZL and ZF rats have lower plasma TG

levels than their VAS controls [116] This is accompanied bythe reduction of the hepatic expression of Srebp-1cmRNA inVA-deficient animals [116] My research group has reportedfor the first time that retinoids synergize with insulin toinduce the expression of Srebp-1c in primary rat hepatocytes[227] Further analysis of the Srebp-1c promoter reveals thatthe previous identified LXREs responsible for mediatinginsulin-induced Srebp-1c expression are also RAREs [227]These observations show that retinoids (nutritional) andinsulin (hormonal) signals converge to regulate the FAsynthesis in the liver

332 The Effects of VA Catabolism on the Regulation of Srebp-1c Expression in Primary Rat Hepatocytes More recentlyretinoids have been proposed to play roles in glucose and lipidmetabolism and to maintain energy homeostasis [228 229]VA (retinol) is reversibly converted into retinal and retinalis irreversibly converted into RA [23] Retinal the precursorof RA production is able to synergize with insulin to inducethe Srebp-1c expression in primary rat hepatocytes [227]This suggests that the dynamic production of RA influencesthe expression of hepatic lipogenic genes It has led us toinvestigate the roles of RA production in the insulin-resistantanimals

In the liver of the Raldh1minusminus mice RA production isreduced in response to a load of retinol [230] The Raldh1minusminusmice are resistant to the development of obesity and insulinresistance after being fed an HFD [26] This is attributed tothe elevation of retinal content due to the lack of conversionof retinal to RA in the adipose tissues of the Raldh1minusminusmice Additionally the liver of the Raldh1minusminus mice hasaltered regulation of the genes for gluconeogenesis andsignificantly attenuated hepatic TG synthesis indicating theimportant role of hepatic VAmetabolism in glucose and lipidhomeostasis [231]

The hepatic expression levels of RALDH1 and RALDH2are induced in mice fed a high-cholesterol diet [232] SREsare located in the promoters of these two genes whichare induced by SREBP-1c overexpression The expression ofSrebp-1c is induced by the oxysterols derived from the high-cholesterol diet [232] This research work demonstrates theinteraction of cholesterol and RA metabolism in the liver Inaddition it has been shown that the level of Raldh1mRNA iselevated in the kidney of dbdb mice [233] Both dbdb miceand ZF rats develop obesity due to the mutation of leptinreceptor [234]

In an attempt to understand the roles of VA metabolismin the states of metabolic diseases we have compared theexpression levels of enzymes responsible for the productionof retinal and RA in the freshly isolated and cultured primaryhepatocytes from ZL rats and ZF rats [45] We have foundthat in the primary rat hepatocytes the enzymes responsiblefor the conversions of retinol to retinal and from retinal toRA are most likely RDH2 and RALDH1 respectively Theexpression levels of Raldh1 mRNA and its protein are higherin hepatocytes from ZF rats than in those from ZL rats[45] When overexpressed RALDH1 introduces the retinal-mediated induction of Srebp-1c in INS-1 cells which do not

ISRN Hepatology 11

respond to retinal in our previous study [227] These resultsindicate that insulin-resistant animals such as ZF rats mayhave alterations in retinoids metabolism

Thus we have hypothesized that the change of RAproduction from the oversupply of dietary VA due to thehyperphagia of ZF rats results in higher Srebp-1c expressionin ZF hepatocytes [45] The elevated SREBP-1c expressioncan further induceRaldh1 expression to create a feed-forwardmechanism that could be one of the reasons responsible forthe increased lipogenesis in the liver of ZF rats All of theseobservations indicate the potential roles of RA metabolismin the development of obesity and insulin resistance whichdeserves to be further studied

4 VArsquos Roles in Mediating Hepatic InsulinAction and Insulin Resistance

41 Insulin and Its Signal Transduction The insulin moleculeis made of two chains linked by one intra- and one interchaindisulfide bonds [235] The insulin receptor is a transmem-brane and heterotetramer tyrosine kinase receptor (two 120572and two 120573 subunits) linked by disulfide bonds as well [236]The binding of insulin to its receptor causes conformationchanges and transphosphorylation of the 120573-subunit tyrosinekinase [237 238] which initiates the signal transduction[239] Protein-protein interactions are involved in the trans-duction of insulin signalThe signal is transduced bymultiplecomponents in a complex network containing cascades ofkinases and phosphatases [240 241] The first intracellularcomponents mediating insulin signals are insulin recep-tor substrates (IRSs) protein molecules phosphorylated byinsulin receptor 120573-subunit and mediating insulin signals[242]

The insulin signal event is further amplified byphosphatidylinositide 3-kinases (PI3K)protein kinaseB (PKBAkt) pathway and GRB2mitogen-activated proteinkinase (MAPK) pathway [243ndash245] Another serinethre-onine kinase that can be activated by PI3K is the atypicalprotein kinase C [246] Human liver expresses severalprotein-tyrosine phosphatases (PTPs) [247] Okadai acid aninhibitor of protein phosphatase type 2A and type 1 inhibitsglycogen synthesis and insulin-stimulated Gck expression inprimary rat hepatocytes indicating that dephosphorylationmechanism may also participate in mediating insulinsignaling [248] These components are shared by insulin-likegrowth factor (IGF) receptor and involved in mediatinginsulin and IGF signals [249]

42 Metabolic Diseases and Insulin Resistance The rise ofthe number of people with one or more metabolic diseasessuch as obesity and diabetes in the world has become apublic health problem [250] The interactions of genetic andenvironmentalnutritional factors may be responsible for thecurrent rise of metabolic diseases The long evolutionaryprocess has equipped human and animal bodieswith a varietyof regulatory mechanisms controlling these interactions [251252] Human diets contain not only energy derived frommacronutrients but also micronutrients and other factors

which may influence the metabolic outcomes The roles ofindividual micronutrients in the development of metabolicdiseases are still unrevealed

One common property of human obesity and NIDDMis insulin resistance in which a given amount of insulinproduces less than normal physiological responses Dietaryfactors and manipulations have been considered to play arole in the development of insulin resistance in humans andanimals For example feeding an HFD to young and insulin-sensitive subjects for two days causes the development ofglucose intolerance [253] In the skeletal muscle of rats fedan HFD for 8 weeks the insulin-induced glucose uptakeis impaired [254] FFAs have been considered the factorsresponsible for HFD-induced leptin and insulin resistance[255ndash257]

43 Hepatic Insulin Resistance and Vicious Cycle The liverplays an essential role in the control of glucose andlipid homeostasis It coordinately regulates the processesin responses to nutritional and hormonal stimuli Insulinplays a major role in directing the liverrsquos metabolic status[258] which is partially attributed to the regulation of theexpression of genes involved in hepatic glucose and lipidmetabolism [215 259]

Insulin controls the expression of a variety of genesinvolved in glycolysis glycogenesis and lipogenesis andgluconeogenesis in the liver [145] Generally hepatic lipidand glucose metabolism is altered with the development ofinsulin resistance in obesity and NIDDM [258] This canbe reflected in the expression of insulin-regulated hepaticgenes for glucose and FA metabolism When the liver isinsulin sensitive insulin stimulates lipogenesis and inhibitsgluconeogenesis For example to regulate hepatic glucosehomeostasis insulin increases the expression of Gck gene[119 120] and Srebp-1c [224] a family member of SREBPswhich regulate the hepatic cholesterol and FA biosynthesisand their homeostasis [260] It suppresses the expressionof Pck1 [142] and G6pc [145] which control the first andlast steps of gluconeogenesis respectively When the liver isinsulin resistant insulin no longer inhibits gluconeogenesisHowever the liver still keeps the elevated lipogenesis Theelevated FA biosynthesis in the insulin-resistant state furtherfacilitates insulin secretion from pancreatic 120573-cells whichprobably enhances lipogenesis and results in a vicious cycle[113 261] The coexistence of the hepatic insulin resistanceand sensitivity at the gene expression level has been observedin rodent obese and diabetic models [215 258] Howeverthe mechanism of this coexistence of insulin sensitivity andresistance has not been revealed [261]

Recently the SREBP cleavage-activating protein gene(Scap) an escort protein necessary for generating nuclearforms of SREBPs has been knocked out in insulin-resistantobob mice [262] Deficiency of hepatic Scap reverses liverlipogenesis and steatosis in obobmice However the plasmalevels of glucose and insulin and the hepatic expression levelsof Pck1 andG6pcwere not different between the control obobmice and the obob mice with liver-specific Scap knockout[262] It seems that the suppression of hepatic FA synthesis

12 ISRN Hepatology

is not sufficient to correct insulin resistance Whether otherfactors play a role in the hepatic insulin resistance is still anopen question

The clinical use of RA-based medicine such asisotretinoin (13-cis RA) caused elevation of plasma TGlevels in human subjects [195ndash197] This increase in plasmaTG levels is also observed in rats [201ndash203] From our VAstatus studies we have shown that VA status affected theobesity development in ZF rats and reduced plasma insulinand TG levels in ZL and ZF rats suggesting improvement ofinsulin sensitivity [116] The hepatic expression of Srebp-1cwas reduced in VA-deficient animals [116] RA synergizeswith insulin to induce the expression of Srebp-1c in primaryrat hepatocytes [227] On the other hand RA treatmentinduces Pck1 expression and attenuates insulin-mediatedsuppression of its expression in primary rat hepatocytes [172]All of these observations demonstrate that RA attenuatesinsulin action (insulin-suppressed Pck1 expression) andstill promotes insulin action (insulin-induced Srebp-1cexpression) in the same primary hepatocytes

44 Possible Mechanism by Which RA Production Causes theDevelopment of the Vicious Cycle in Hepatocytes Could RAor other metabolites from VA catabolism be a factor thatcontributes to the hepatic insulin resistance and the viciouscycleUsing the regulation ofPck1 and Srebp-1c as themodel Ihave come upwith the following scheme to show that retinoidmetabolism could be a factor that causes the vicious cycle inthe liver As shown in Figure 3(a) in insulin-sensitive hepa-tocytes RA derived from retinal coordinates with insulin toregulate the expression of Srebp-1c and Pck1 The SREBP-1cprotein is processed to mature form a step that can be facili-tated by insulin [263] The mature form of SREBP-1c entersinto the nucleus and induces the mRNA levels of Raldh1and Fas which are respectively transcribed into RALDH1and FAS RALDH1 catalyzes the conversion of retinal to RAFAS catalyzes the synthesis of palmitate which is esterifiedinto TGs or elongated to longer FAs The Pck1 mRNA isused to translate into PEPCK-C protein which contributesto glucogenogenesis In the insulin-resistant hepatocytes asshown in Figure 3(b) the elevation of Raldh1 expressiondue to leptin deficiency [45] or induction of SREBP-1c byhigh-cholesterol feeding [232] induces the production of RAThe elevated RA levels will stimulate the transcription ofSrebp-1c and Pck1 This leads to more production of SREBP-1c and its mature form in the presence of higher insulinlevels in the insulin-resistant state The induction of SREBP-1c further enhances the transcription of Raldh1 and Fas andtheir corresponding proteins for the production of moreRAs and FAs respectively The RA production and SREBP-1c expression form a feed-forward cycle which causes moreTG and RA production in the insulin-resistant liver At thesame time more of the PEPCK-C protein is generated dueto the elevated Pck1 transcription by RA stimulation whichis not responsive to insulin inhibition as we have shown in[172] This leads to elevated gluconeogenesis in the insulin-resistant liver Eventually the phenotypes appear as if insulin

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1cRetinal

RALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(a) Insulin-sensitive hepatocytes

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1c

RetinalRALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(b) Insulin-resistant hepatocytes

Figure 3 The effects of RA on the insulin-regulated Srebp-1cand Pck1 expression levels the protein levels of SREBP-1c theexpression levels of Raldh1 and Fas and the fatty acid synthesisand gluconeogenesis in insulin-sensitive (a) and insulin-resistant (b)hepatocytes Please see the text in this paper for description Uparrows next to the text indicate induction The intensified weight ofthe lines indicates the induction of that part of the pathway

no longer suppresses gluconeogenesis while it still stimulatesFA synthesis in the insulin-resistant state

5 Perspectives and Future Directions

I have proposed a mechanism by which VA metabolismcontributes to the development of hepatic insulin resistanceIt explains some observations reported in the previous studiesof rodent obese and diabetic models [215 258] However itleavesmore open questionsThefirst one iswhat the initiationfactor is So far the elevated expression of Raldh1 mRNA inthe liver has been observed in ZF rats [45] and mice fed ahigh-cholesterol diet [232] These two conditions cause a lotof physiological changes such as overfeeding in ZF rats andchange of cholesterol biosynthesis in response to the feedingof high-cholesterol diet Knocking down Raldh1 specificallyin hepatocytes is needed to answer these questions The

ISRN Hepatology 13

second question is whether RA synthesis in hepatocytesis a regulated process in response to dietary or hormonalstimulations If Raldh1 is a downstream gene of SREBP-1cit should be regulated when the SREBP-1c level changes Asthe expression of Srebp-1c responds to insulin stimulation andoxysterols the regulation of Raldh1 expression in the livershould be studied The third question is why it is RALDH1but not other RALDHs Specific inhibitors of RALDHsmay be needed to answer this question Last question iswhether we can attenuate insulin resistance by suppressingthe RALDH1 activity in the liver It has been shown thatRaldh1minusminus mice are still insulin sensitive when they are onan HFD [26] This has been attributed to the effects on theadipogenesis However the liver of those knockout mice hasreduced lipid synthesis [231] Further studies are warrantedto answer all of these questions Hopefully it can become anintervention point for the treatment of insulin resistance andmetabolic diseases

Acknowledgments

This work was financially supported by a research grantfrom Allen Foundation Inc (to Guoxun Chen) a start-up fund from the University of Tennessee at Knoxville (toGuoxun Chen) and a Scientist Development Grant fromthe AmericanHeart Association (09SDG2140003 to GuoxunChen) The author thanks his colleague Dr Lauren Gellar forreading through this paper and offering her edits

References

[1] F G Hopkins ldquoFeeding experiments illustrating the impor-tance of accessory factors in normal dietariesrdquo The Journal ofPhysiology vol 44 no 5-6 pp 425ndash460 1912

[2] K J Carpenter ldquoA short history of nutritional science part 3(1912ndash1944)rdquo Journal of Nutrition vol 133 no 10 pp 3023ndash30322003

[3] E V McCollum and M Davis ldquoThe necessity of certain lipinsin the diet during growthrdquo Journal of Biological Chemistry vol15 no 1 pp 167ndash175 1913

[4] T B Osborne and L B Mendel ldquoFeeding experiments with fat-free food mixturesrdquo Journal of Biological Chemistry vol 12 no1 pp 81ndash89 1912

[5] R D Semba ldquoOn the lsquoDiscoveryrsquo of Vitamin Ardquo Annals ofNutrition and Metabolism vol 61 no 3 pp 192ndash198 2012

[6] R Blomhoff and H K Blomhoff ldquoOverview of retinoidmetabolism and functionrdquo Journal of Neurobiology vol 66 no7 pp 606ndash630 2006

[7] A Sommer ldquoVitamin A deficiency and clinical disease anhistorical overviewrdquo Journal of Nutrition vol 138 no 10 pp1835ndash1839 2008

[8] K J Rothman L L Moore M R Singer U-S Nguyen SMannino and A Milunsky ldquoTeratogenicity of high vitamin Aintakerdquo The New England Journal of Medicine vol 333 no 21pp 1369ndash1373 1995

[9] S Bershad A Rubinstein and J R Paterniti Jr ldquoChanges inplasma lipids and lipoproteins during isotretinoin therapy foracnerdquoThe New England Journal of Medicine vol 313 no 16 pp981ndash985 1985

[10] N Rodondi R Darioli A-A Ramelet et al ldquoHigh risk forhyperlipidemia and the metabolic syndrome after an episodeof hypertriglyceridemia during 13-cis retinoic acid therapy foracne a pharmacogenetic studyrdquo Annals of Internal Medicinevol 136 no 8 pp 582ndash589 2002

[11] H-U Klor A Weizel M Augustin et al ldquoThe impact oforal vitamin A derivatives on lipid metabolism what recom-mendations can be derived for dealing with this issue in thedaily dermatological practicerdquo Journal of the German Societyof Dermatology vol 9 no 8 pp 600ndash607 2011

[12] R M Russell ldquoThe vitamin A spectrum from deficiency totoxicityrdquoThe American Journal of Clinical Nutrition vol 71 no4 pp 878ndash884 2000

[13] A C Ross B Caballero R J Cousins K L Tucker and T RZiegler Modern Nutrition in Health and Diseases 11th edition2012

[14] E H Harrison ldquoMechanisms of digestion and absorption ofdietary vitamin Ardquo Annual Review of Nutrition vol 25 no 1pp 87ndash103 2005

[15] M R Lakshman ldquoAlpha and omega of carotenoid cleavagerdquoJournal of Nutrition vol 134 no 1 pp 241ndash245 2004

[16] I Potrykus ldquoNutritionally enhanced rice to combat malnutri-tion disorders of the poorrdquo Nutrition Reviews vol 61 no 6 ppS101ndashS104 2003

[17] A Wyss ldquoCarotene oxygenases a new family of double bondcleavage enzymesrdquo Journal of Nutrition vol 134 no 1 pp 246ndash250 2004

[18] R Kawaguchi J Yu J Honda et al ldquoA membrane receptor forretinol binding protein mediates cellular uptake of vitamin ArdquoScience vol 315 no 5813 pp 820ndash825 2007

[19] P Alapatt F Guo S M Komanetsky et al ldquoLiver retinoltransporter and receptor for serum retinol-binding protein(RBP4)rdquo Journal of Biological Chemistry vol 288 no 2 pp1250ndash1265 2013

[20] A R Moise N Noy K Palczewski and W S Blaner ldquoDeliveryof retinoid-based therapies to target tissuesrdquo Biochemistry vol46 no 15 pp 4449ndash4458 2007

[21] G Duester ldquoFamilies of retinoid dehydrogenases regulatingvitamin A function Production of visual pigment and retinoicacidrdquo European Journal of Biochemistry vol 267 no 14 pp4315ndash4324 2000

[22] M Theodosiou V Laudet and M Schubert ldquoFrom carrotto clinic an overview of the retinoic acid signaling pathwayrdquoCellular andMolecular Life Sciences vol 67 no 9 pp 1423ndash14452010

[23] J L Napoli ldquoInteractions of retinoid binding proteins andenzymes in retinoidmetabolismrdquoBiochimica et BiophysicaActavol 1440 no 2-3 pp 139ndash162 1999

[24] X Chai M H E M Boerman Y Zhai and J L NapolildquoCloning of a cDNA for liver microsomal retinol dehydro-genase A tissue-specific short-chain alcohol dehydrogenaserdquoJournal of Biological Chemistry vol 270 no 8 pp 3900ndash39041995

[25] B X Wu G Moiseyev Y Chen B Rohrer R K Crouch andJ-XMa ldquoIdentification of RDH10 an all-trans retinol dehydro-genase in retinal Muller cellsrdquo Investigative Ophthalmology andVisual Science vol 45 no 11 pp 3857ndash3862 2004

[26] O Ziouzenkova G Orasanu M Sharlach et al ldquoRetinalde-hyde represses adipogenesis and diet-induced obesityrdquo NatureMedicine vol 13 no 6 pp 695ndash702 2007

14 ISRN Hepatology

[27] J L Napoli ldquoPhysiological insights into all-trans-retinoic acidbiosynthesisrdquo Biochimica et Biophysica Acta vol 1821 no 1 pp152ndash167 2012

[28] G Wolf ldquoTissue-specific increases in endogenous all-transretinoic acid possible contributing factor in ethanol toxicityrdquoNutrition Reviews vol 68 no 11 pp 689ndash692 2010

[29] P V Bhat J Labrecque JM Boutin A Lacroix andA YoshidaldquoCloning of a cDNA encoding rat aldehyde dehydrogenase withhigh activity for retinal oxidationrdquoGene vol 166 no 2 pp 303ndash306 1995

[30] M Lin M Zhang M Abraham S M Smith and J LNapoli ldquoMouse retinal dehydrogenase 4 (RALDH4) molecularcloning cellular expression and activity in 9-cis-retinoic acidbiosynthesis in intact cellsrdquo Journal of Biological Chemistry vol278 no 11 pp 9856ndash9861 2003

[31] F A Mic A Molotkov X Fan A E Cuenca and GDuester ldquoRALDH3 a retinaldehyde dehydrogenase that gener-ates retinoic acid is expressed in the ventral retina otic vesicleand olfactory pit during mouse developmentrdquo Mechanisms ofDevelopment vol 97 no 1-2 pp 227ndash230 2000

[32] X Wang P Penzes and J L Napoli ldquoCloning of a cDNAencoding an aldehyde dehydrogenase and its expression inEscherichia coli recognition of retinal as substraterdquo Journal ofBiological Chemistry vol 271 no 27 pp 16288ndash16293 1996

[33] A Molotkov and G Duester ldquoGenetic evidence that retinalde-hyde dehydrogenase Raldh1 (Aldh1a1) functions downstreamof alcohol dehydrogenase Adh1 in metabolism of retinol toretinoic acidrdquo Journal of Biological Chemistry vol 278 no 38pp 36085ndash36090 2003

[34] G Elizondo J Corchero E Sterneck and F J GonzalezldquoFeedback inhibition of the retinaldehyde dehydrogenase geneALDH1 by retinoic acid through retinoic acid receptor 120572and CCAATenhancer-binding protein 120573rdquo Journal of BiologicalChemistry vol 275 no 50 pp 39747ndash39753 2000

[35] G Elizondo I M Medina-Dıaz R Cruz F J Gonzalez and LVega ldquoRetinoic acid modulates retinaldehyde dehydrogenase 1gene expression through the induction of GADD153-CEBP120573interactionrdquo Biochemical Pharmacology vol 77 no 2 pp 248ndash257 2009

[36] K Fujiwara M Kikuchi K Horiguchi et al ldquoEstrogen receptoralpha regulates retinaldehyde dehydrogenase 1 expression in ratanterior pituitary cellsrdquo Endocrine Journal vol 56 no 8 pp963ndash973 2009

[37] K Fujiwara F Maekawa M Kikuchi S Takigami T Yadaand T Yashiro ldquoExpression of retinaldehyde dehydrogenase(RALDH)2 and RALDH3 but not RALDH1 in the developinganterior pituitary glands of ratsrdquo Cell and Tissue Research vol328 no 1 pp 129ndash135 2007

[38] GWolf ldquoThe enzymatic cleavage of 120573-carotene still controver-sialrdquo Nutrition Reviews vol 53 no 5 pp 134ndash137 1995

[39] S Abu-Abed P Dolle D Metzger B Beckett P Chambonand M Petkovich ldquoThe retinoic acid-metabolizing enzymeCYP26A1 is essential for normal hindbrain patterning verte-bral identity and development of posterior structuresrdquo Genesand Development vol 15 no 2 pp 226ndash240 2001

[40] M A Leo S Iida and C S Lieber ldquoRetinoic acid metabolismby a system reconstituted with cytochrome P-450rdquo Archives ofBiochemistry and Biophysics vol 234 no 1 pp 305ndash312 1984

[41] MA Leo JM Lasker J L Raucy C-I KimM Black andC SLieber ldquoMetabolism of retinol and retinoic acid by human livercytochrome P450IIC8rdquoArchives of Biochemistry and Biophysicsvol 269 no 1 pp 305ndash312 1989

[42] R Quere A Baudet B Cassinat et al ldquoPharmacogenomicanalysis of acute promyelocytic leukemia cells highlightsCYP26cytochrome metabolism in differential all-trans retinoic acidsensitivityrdquo Blood vol 109 no 10 pp 4450ndash4460 2007

[43] J AWhite B Beckett-Jones Y-D Guo et al ldquocDNA cloning ofhuman retinoic acid-metabolizing enzyme (hP450RAI) identi-fies a novel family of cytochromes p450 (CYP26)rdquo Journal ofBiological Chemistry vol 272 no 30 pp 18538ndash18541 1997

[44] Y Zhang R Zolfaghari Reza and A C Ross ldquoMultiple retinoicacid response elements cooperate to enhance the inducibility ofCYP26A1 gene expression in liverrdquo Gene vol 464 no 1-2 pp32ndash43 2010

[45] Y Li Y Zhang R Li et al ldquoThe hepatic raldh1 expression iselevated in Zucker fatty rats and its over-expression introducedthe retinal-induced Srebp-1c expression in INS-1 cellsrdquo PLoSONE vol 7 no 9 Article ID e45210 2012

[46] R M Evans ldquoThe nuclear receptor superfamily a Rosetta stonefor physiologyrdquo Molecular Endocrinology vol 19 no 6 pp1429ndash1438 2005

[47] P Chambon ldquoA decade of molecular biology of retinoic acidreceptorsrdquo FASEB Journal vol 10 no 9 pp 940ndash954 1996

[48] D J Mangelsdorf and RM Evans ldquoThe RXR heterodimers andorphan receptorsrdquo Cell vol 83 no 6 pp 841ndash850 1995

[49] J E Balmer and R Blomhoff ldquoA robust characterization ofretinoic acid response elements based on a comparison of sitesin three speciesrdquo Journal of Steroid Biochemistry and MolecularBiology vol 96 no 5 pp 347ndash354 2005

[50] R Kurokawa J DiRenzo M Boehm et al ldquoRegulation ofretinoid signalling by receptor polarity and allosteric control ofligand bindingrdquo Nature vol 371 no 6497 pp 528ndash531 1994

[51] A Cvekl and W-L Wang ldquoRetinoic acid signaling in mam-malian eye developmentrdquo Experimental Eye Research vol 89no 3 pp 280ndash291 2009

[52] V Dupe M Davenne J Brocard et al ldquoIn vivo functional anal-ysis of the Hoxa-1 31015840 retinoic acid response element (31015840RARE)rdquoDevelopment vol 124 no 2 pp 399ndash410 1997

[53] A C Ross ldquoRetinoid production and catabolism role of dietin regulating retinol esterification and retinoic acid oxidationrdquoJournal of Nutrition vol 133 no 1 pp 291ndash296 2003

[54] T Moore and P D Holmes ldquoThe production of experimentalvitamin A deficiency in rats andmicerdquo Laboratory Animals vol5 no 2 pp 239ndash250 1971

[55] A C Ross and E H Harrison ldquoVitamin A and carotenoidsrdquoin Handbook of Vitamins D E McCormick R R Rucker J WSuttie et al Eds CRC Press Boca Raton Fla USA 4th edition2006

[56] A Chawta J J Repa R M Evans and D J MangelsdorfldquoNuclear receptors and lipid physiology opening the x-filesrdquoScience vol 294 no 5548 pp 1866ndash1870 2001

[57] C K Glass and M G Rosenfeld ldquoThe coregulator exchangein transcriptional functions of nuclear receptorsrdquo Genes andDevelopment vol 14 no 2 pp 121ndash141 2000

[58] A L Bookout Y Jeong M Downes R T Yu R M EvansandD JMangelsdorf ldquoAnatomical profiling of nuclear receptorexpression reveals a hierarchical transcriptional networkrdquo Cellvol 126 no 4 pp 789ndash799 2006

[59] B Mascrez M Mark W Krezel et al ldquoDifferential contribu-tions of AF-1 andAF-2 activities to the developmental functionsof RXR120572rdquo Development vol 128 no 11 pp 2049ndash2062 2001

[60] D Li T Li F Wang H Tian and H H Samuels ldquoFunctionalevidence for retinoid X receptor (RXR) as a nonsilent partner

ISRN Hepatology 15

in the thyroid hormone receptorRXR heterodimerrdquoMolecularand Cellular Biology vol 22 no 16 pp 5782ndash5792 2002

[61] F M Sladek W Zhong E Lai and J E Darnell Jr ldquoLiver-enriched transcription factor HNF-4 is a novel member ofthe steroid hormone receptor superfamilyrdquo Genes and Develop-ment vol 4 no 12 pp 2353ndash2365 1990

[62] K Yamagata H Furuta N Oda et al ldquoMutations in thehepatocyte nuclear factor-4120572 gene inmaturity-onset diabetes ofthe young (MODY1)rdquo Nature vol 384 no 6608 pp 458ndash4601996

[63] M Stoffel and S ADuncan ldquoThematurity-onset diabetes of theyoung (MODY1) transcription factor HNF4120572 regulates expres-sion of genes required for glucose transport and metabolismrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 24 pp 13209ndash13214 1997

[64] M Lehto P-O Bitzen B Isomaa et al ldquoMutation in the HNF-4120572 gene affects insulin secretion and triglyceride metabolismrdquoDiabetes vol 48 no 2 pp 423ndash425 1999

[65] G P Hayhurst Y-H Lee G Lambert J M Ward and F JGonzalez ldquoHepatocyte nuclear factor 4120572 (Nuclear receptor 2A1)is essential formaintenance of hepatic gene expression and lipidhomeostasisrdquo Molecular and Cellular Biology vol 21 no 4 pp1393ndash1403 2001

[66] U Roth K Jungermann and T Kietzmann ldquoActivation ofglucokinase gene expression by hepatic nuclear factor 4120572 inprimary hepatocytesrdquo Biochemical Journal vol 365 no 1 pp223ndash228 2002

[67] S Mandard R Stienstra P Escher et al ldquoGlycogen synthase2 is a novel target gene of peroxisome proliferator-activatedreceptorsrdquo Cellular and Molecular Life Sciences vol 64 no 9pp 1145ndash1157 2007

[68] F Rajas A Gautier I Bady S Montano and G MithieuxldquoPolyunsaturated fatty acyl coenzyme a suppress the glucose-6-phosphatase promoter activity bymodulating the DNA bindingof hepatocyte nuclear factor 4120572rdquo Journal of Biological Chemistryvol 277 no 18 pp 15736ndash15744 2002

[69] B Viollet A Kahn and M Raymondjean ldquoProtein kinase A-dependent phosphorylation modulates DNA-binding activityof hepatocyte nuclear factor 4rdquoMolecular and Cellular Biologyvol 17 no 8 pp 4208ndash4219 1997

[70] L Palanker J M Tennessen G Lam and C S Thum-mel ldquoDrosophila HNF4 regulates lipid mobilization and 120573-oxidationrdquo Cell Metabolism vol 9 no 3 pp 228ndash239 2009

[71] A Miura K Yamagata M Kakei et al ldquoHepatocyte nuclearfactor-4120572 is essential for glucose-stimulated insulin secretion bypancreatic 120573-cellsrdquo Journal of Biological Chemistry vol 281 no8 pp 5246ndash5257 2006

[72] R Bartoov-Shifman R Hertz H Wang C B Wollheim JBar-Tana and M D Walker ldquoActivation of the insulin genepromoter through a direct effect of hepatocyte nuclear factor4120572rdquo Journal of Biological Chemistry vol 277 no 29 pp 25914ndash25919 2002

[73] H Wang P Maechler P A Antinozzi K A Hagenfeldt andC B Wollheim ldquoHepatocyte nuclear factor 4120572 regulates theexpression of pancreatic 120573-cell genes implicated in glucosemetabolism and nutrient-induced insulin secretionrdquo Journal ofBiological Chemistry vol 275 no 46 pp 35953ndash35959 2000

[74] K Reue T Leff and J L Breslow ldquoHuman apolipoproteinCIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factorsrdquo Journal ofBiological Chemistry vol 263 no 14 pp 6857ndash6864 1988

[75] T Leff K Reue A Melian H Culver and J L BreslowldquoA regulatory element in the apoCIII promoter that directshepatic specific transcription binds to proteins in expressingand nonexpressing cell typesrdquo Journal of Biological Chemistryvol 264 no 27 pp 16132ndash16137 1989

[76] S N Lavrentiadou M Hadzopoulou-Cladaras D Kardassisand V I Zannis ldquoBinding specificity and modulation of thehuman apocIII promoter activity by heterodimers of ligand-dependent nuclear receptorsrdquo Biochemistry vol 38 no 3 pp964ndash975 1999

[77] T R Magee Y Cai M E El-Houseini J Locker and Y-JY Wan ldquoRetinoic acid mediates down-regulation of the 120572-fetoprotein gene through decreased expression of hepatocytenuclear factorsrdquo Journal of Biological Chemistry vol 273 no 45pp 30024ndash30032 1998

[78] A Qian Y Cai T R Magee and Y J Y Wan ldquoIdentificationof retinoic acid-responsive elements on the HNF1alpha andHNF4alpha genesrdquo Biochemical and Biophysical Research Com-munications vol 276 no 3 pp 837ndash842 2000

[79] H Nakshatri and P Chambon ldquoThe directly repeatedRG(GT)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites forRAR RXR HNF-4 and ARP-1 homo- and heterodimersrdquoJournal of Biological Chemistry vol 269 no 2 pp 890ndash9021994

[80] T Makita G Hernandez-Hoyos T H-P Chen H Wu E VRothenberg and H M Sucov ldquoA developmental transition indefinitive erythropoiesis erythropoietin expression is sequen-tially regulated by retinoic acid receptors andHNF4rdquoGenes andDevelopment vol 15 no 7 pp 889ndash901 2001

[81] T I Kambe J Tada-Kambe Y Kuge Y Yamaguchi-Iwai MNagao and R Sasaki ldquoRetinoic acid stimulates erythropoietingene transcription in embryonal carcinoma cells through thedirect repeat of a steroidthyroid hormone receptor responseelement half-site in the hypoxia-response enhancerrdquo Blood vol96 no 9 pp 3265ndash3271 2000

[82] F-J Lin J Qin K Tang S Y Tsai and M-J Tsai ldquoCoup drsquoEtatan orphan takes controlrdquo Endocrine Reviews vol 32 no 3 pp404ndash421 2011

[83] L-H Wang S Y Tsai R G Cook W G Beattie M-J Tsaiand BW OrsquoMalley ldquoCOUP transcription factor is a member ofthe steroid receptor superfamilyrdquoNature vol 340 no 6229 pp163ndash166 1989

[84] X Leng A J Cooney S Y Tsai and M-J Tsai ldquoMolecularmechanisms of COUP-TF-mediated transcriptional repressionevidence for transrepression and active repressionrdquo Molecularand Cellular Biology vol 16 no 5 pp 2332ndash2340 1996

[85] L Li X Xie J Qin et al ldquoThe nuclear orphan receptorCOUP-TFII plays an essential role in adipogenesis glucosehomeostasis and energy metabolismrdquo Cell Metabolism vol 9no 1 pp 77ndash87 2009

[86] F A Pereira Q Yuhong G Zhou M-J Tsai and S YTsai ldquoThe orphan nuclear receptor COUP-TFII is required forangiogenesis and heart developmentrdquo Genes and Developmentvol 13 no 8 pp 1037ndash1049 1999

[87] N Takamoto I Kurihara K Lee F J DeMayo M-J Tsai andS Y Tsai ldquoHaploinsufficiency of chicken ovalbumin upstreampromoter transcription factor II in female reproductionrdquoMolec-ular Endocrinology vol 19 no 9 pp 2299ndash2308 2005

[88] P Zhang M Bennoun C Gogard et al ldquoExpression of COUP-TFII in metabolic tissues during developmentrdquo Mechanisms ofDevelopment vol 119 no 1 pp 109ndash114 2002

16 ISRN Hepatology

[89] Z Xu S Yu C-H Hsu J Eguchi and E D Rosen ldquoTheorphan nuclear receptor chicken ovalbumin upstream pro-moter-transcription factor II is a critical regulator of adipogene-sisrdquoProceedings of theNationalAcademy of Sciences of theUnitedStates of America vol 105 no 7 pp 2421ndash2426 2008

[90] P Bardoux P Zhang D Flamez et al ldquoEssential role of chickenovalbumin upstreampromoter-transcription factor II in insulinsecretion and insulin sensitivity revealed by conditional geneknockoutrdquo Diabetes vol 54 no 5 pp 1357ndash1363 2005

[91] G Achatz B Holzl R Speckmayer C Hauser F Sandhoferand B Paulweber ldquoFunctional domains of the human orphanreceptor ARP-1COUP-TFII involved in active repression andtransrepressionrdquo Molecular and Cellular Biology vol 17 no 9pp 4914ndash4932 1997

[92] S A Kliewer K Umesono R A Heyman D J MangelsdorfJ A Dyck and R M Evans ldquoRetinoid X receptor-COUP-TFinteractionsmodulate retinoic acid signalingrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol89 no 4 pp 1448ndash1452 1992

[93] A J Cooney S Y Tsai BW OrsquoMalley andM-J Tsai ldquoChickenovalbumin upstreampromoter transcription factor (COUP-TF)dimers bind to different GGTCA response elements allowingCOUP-TF to repress hormonal induction of the vitamin D3thyroid hormone and retinoic acid receptorsrdquo Molecular andCellular Biology vol 12 no 9 pp 4153ndash4163 1992

[94] SW Kruse K Suino-Powell X E Zhou et al ldquoIdentification ofCOUP-TFII orphannuclear receptor as a retinoic acid-activatedreceptorrdquo PLoS Biology vol 6 no 9 Article ID e227 2008

[95] J P Berger T E Akiyama and P T Meinke ldquoPPARs thera-peutic targets for metabolic diseaserdquo Trends in PharmacologicalSciences vol 26 no 5 pp 244ndash251 2005

[96] JM Peters andF J Gonzalez ldquoSorting out the functional role(s)of peroxisome proliferator-activated receptor-120573120575 (PPAR120573120575)in cell proliferation and cancerrdquo Biochimica et Biophysica Actavol 1796 no 2 pp 230ndash241 2009

[97] A Tenenbaum and E Fisman ldquoBalanced pan-PPAR activatorbezafibrate in combination with statin comprehensive lipidscontrol and diabetes preventionrdquo Cardiovascular Diabetologyvol 11 no 1 article 140 2012

[98] O Braissant F Foufelle C Scotto M Dauca and W WahlildquoDifferential expression of peroxisome proliferator-activatedreceptors (PPARs) tissue distribution of PPAR-120572 -120573 and -120574 inthe adult ratrdquo Endocrinology vol 137 no 1 pp 354ndash366 1996

[99] H Higashiyama A N Billin Y Okamoto M Kinoshita andS Asano ldquoExpression profiling of Peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues usingtissue microarrayrdquo Histochemistry and Cell Biology vol 127 no5 pp 485ndash494 2007

[100] P S Jones R Savory P Barratt et al ldquoChromosomal local-isation inducibility tissue-specific expression and strain dif-ferences in three murine peroxisome-proliferator-activated-receptor genesrdquo European Journal of Biochemistry vol 233 no1 pp 219ndash226 1995

[101] S A Kliewer B M Forman B Blumberg et al ldquoDifferentialexpression and activation of a family of murine peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no15 pp 7355ndash7359 1994

[102] E E Girroir H E Hollingshead P He B Zhu G H Perdewand J M Peters ldquoQuantitative expression patterns of peroxi-some proliferator-activated receptor-120573120575 (PPAR120573120575) protein in

micerdquo Biochemical and Biophysical Research Communicationsvol 371 no 3 pp 456ndash461 2008

[103] P Escher O Braissant S Basu-Modak L Michalik W Wahliand B Desvergne ldquoRat PPARs quantitative analysis in adult rattissues and regulation in fasting and refeedingrdquo Endocrinologyvol 142 no 10 pp 4195ndash4202 2001

[104] D Auboeuf J Rieusset L Fajas et al ldquoTissue distributionand quantification of the expression of mRNAs of peroxi-some proliferator-activated receptors and liver X receptor-120572 inhumans no alteration in adipose tissue of obese and NIDDMpatientsrdquo Diabetes vol 46 no 8 pp 1319ndash1327 1997

[105] N ShawM Elholm andN Noy ldquoRetinoic acid is a high affinityselective ligand for the peroxisome proliferator-activated recep-tor 120573120575rdquo Journal of Biological Chemistry vol 278 no 43 pp41589ndash41592 2003

[106] G Wolf ldquoRetinoic acid as cause of cell proliferation or cellgrowth inhibition depending on activation of one of twodifferent nuclear receptorsrdquoNutrition Reviews vol 66 no 1 pp55ndash59 2008

[107] T T Schug D C Berry N S Shaw S N Travis and N NoyldquoOpposing effects of retinoic acid on cell growth result fromalternate activation of two different nuclear receptorsrdquo Cell vol129 no 4 pp 723ndash733 2007

[108] D C Berry and N Noy ldquoAll-trans-retinoic acid repressesobesity and insulin resistance by activating both peroxisomeproliferation-activated receptor 120573120575 and retinoic acid receptorrdquoMolecular and Cellular Biology vol 29 no 12 pp 3286ndash32962009

[109] D C Berry D DeSantis H Soltanian C M Croniger andN Noy ldquoRetinoic acid upregulates preadipocyte genes to blockadipogenesis and suppress diet-induced obesityrdquo Diabetes vol61 no 5 pp 1112ndash1121 2012

[110] M G Borland C Khozoie P P Albrecht et al ldquoStableover-expression of PPAR120573120575 and PPAR120574 to examine receptorsignaling in human HaCaT keratinocytesrdquo Cellular Signallingvol 23 no 12 pp 2039ndash2050 2011

[111] S E OrsquoSullivan and D A Kendall ldquoCannabinoid activationof peroxisome proliferator-activated receptors potential formodulation of inflammatory diseaserdquo Immunobiology vol 215no 8 pp 611ndash616 2010

[112] Z C Yan D Y Liu L L Zhang et al ldquoExercise reduces adiposetissue via cannabinoid receptor type 1 which is regulated byperoxisome proliferator-activated receptor-120575rdquo Biochemical andBiophysical Research Communications vol 354 no 2 pp 427ndash433 2007

[113] J D McGarry ldquoWhat if Minkowski had been ageusic Analternative angle on diabetesrdquo Science vol 258 no 5083 pp766ndash770 1992

[114] TMoore ldquoVitaminA and carotene the vitaminA reserve of theadult human being in health and diseaserdquo Biochemical Journalvol 31 no 1 pp 155ndash164 1937

[115] GWolfMD Lane and B C Johnson ldquoStudies on the functionof vitamin A in metabolismrdquo Journal of Biological Chemistryvol 225 no 2 pp 995ndash1008 1957

[116] Y Zhang R Li Y Li W Chen S Zhao and G Chen ldquoVitaminA status affects obesity development and hepatic expression ofkey genes for fuel metabolism in Zucker fatty ratsrdquoBiochemistryand Cell Biology vol 90 no 4 pp 548ndash557 2012

[117] M Singh V N Singh and T A Venkitasubramanian ldquoEarlyeffects of feeding excess vitamin A hepatic glycogen bloodlactic acid plasma nefa and glucose tolerance in ratsrdquo LifeSciences vol 7 no 5 pp 239ndash247 1968

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Hepatology 5

COUP-TFINR2F1ErbA-related protein-3 (EAR3) COUP-TFIINR2F2apolipoprotein-AI regulatory protein-1 (ARP1)and COUP-TFIIINR2F6 (EAR2) [82] COUP-TFs are con-servative among all species with the ligand-binding domainsof COUP-TFI or -II being identical in vertebrates

The cloning and analysis of COUP-TFII (gene NR2F2)cDNA from Hela cells indicate that it is a member ofnuclear receptor superfamily [83] COUP-TFII seems to berequired earlier in the development processes than COUP-TFI COUP-TFII has been thought to suppress gene expres-sion [84] It has been shown to function in a variety of biolog-ical processes such as development cellular differentiationgrowth and metabolic homeostasis [85] Deletion of Nr2f2in mouse is lethal [82] It has been shown that mice withhomozygous deletion of Nr2f2 die at around E10 probablydue to severe hemorrhage and edema and only one-thirdof the heterozygote mice survive before weaning [86] Nr2f2heterozygous pups have growth retardation in comparisonwith their wild-type controls [87] Adult Nr2f2 heterozygousknockout mice have lower body weight and basal plasmainsulin level but higher insulin sensitivity than that of theirwild-type controls [85] They also exhibit resistance to high-fat diet- (HFD-) induced obesity and improved glucosetolerance [85]

COUP-TFII expression can be detected in a variety ofmetabolic active tissues and organs [88] Since heterozygousmice withNr2f2 deletion have improved glucose homeostasisand increased energy expenditure this indicates that COUP-TFII also plays roles in white adipose tissues developmentand energy metabolism [85] COUP-TFII may suppressadipogenesis via inhibiting the expression of genes foradipocyte differentiation such as the expression of sterolregulatory element-binding protein-1c (SREBP1c) PPAR120574and CCAATenhancer-binding protein 120572 (CEBP120572) [89]COUP-TFII regulates the expression of insulin gene andseveral other genes involved in glucose and lipid metabolismin pancreatic 120573-cells Heterozygous mice with Nr2f2 deletionin pancreatic 120573-cells have impaired glucose sensitivity andabnormal insulin secretion [90]

COUP-TFII regulates gene expression via both protein-protein and protein-DNA interactions [76] For exampleCOUP-TFII binds to hormone response elements (HREs)recognized by other nuclear receptors and in turnmodulatesthe expression of these genes It has been shown that COUP-TFII can bind to a variety of HREs that contain direct orinverted imperfect AGGTCA repeats with various spacesCOUP-TFII can also interact with the common partners orgeneral transcriptional factors to modulate gene expression[84 91] For example the amount of RXR available for theformation of high-affinity DNA-binding complexes of thethyroid hormoneRAR subfamily can be limited COUP-TFIIcan also actively silence basal and activated transcriptionlikely through direct interaction with TFIIB or other generaltranscription factors [84]Therefore COUP-TFII may antag-onize the functions of other hormones and in turn alter thecellular responses to multiple-hormone signaling pathwaysand it can have profound effects on metabolic homeostasis

COUP-TF protein interacts with RXR120572 to form het-erodimer [92] Using RXR120572 cDNA probe COUP-TFs were

identified to bind to RAREs The original COUP-TF-bindingsite in the ovalbumin gene is also a RARE that is repressedby COUP-TF [93] On the other hand RXR120572 and COUP-TFII can bind to the same DR1 element individually or inthe heterodimeric form in an electrophoresis mobility shiftassay (EMSA) Cotransfection of COUP-TFII and RXR120572suppresses RXR-mediated activation of CRBPII promoterwhich contains one RARE [92] COUP-TFs are involved inthe modulation of RAR- and RXR-mediated responses toretinoids during embryogenesis [84] Recently COUP-TFIIhas been identified as a low-affinity RA receptor The ligandbinding of COUP-TFII is in an autorepressed conformationAt high concentrations RA is able to promote COUP-TFIIto recruit coactivators and to activate a COUP-TF reporterconstruct [94] These observations suggest a linkage betweenRA and COUP-TFII signaling pathways

145 PPAR120573120575 forMediating RAResponses PPARs aremem-bers of nuclear receptor superfamily They take part in theregulation of a variety of physiological functions such as celldifferentiation metabolism and immune functions [95] Sofar three PPAR isoforms PPAR120572 PPAR120573120575 and PPAR120574are identified and reported The expression of PPAR120573120575 isubiquitous which can be detected in a lot of cell typesand tissues [96 97] In rats PPAR120573120575 mRNA and proteinsare expressed ubiquitously and often coexpressed with otherPPARs [98] Similar expression profiles are observed inmice [99ndash101] In mice PPAR120573120575 protein can be detectedin a variety of tissues with high expression levels in thesmall intestine skin and liver [102] The expression levels ofPPAR120573120575mRNA and protein in the liver of rats fasted for 12hours are reduced and increased upon refeeding for 45 hours[103]The expression of low levels of human PPAR120573120575mRNAcan be detected in the adipose tissues the skeletal muscle theliver the kidney and the intestines [104]

It has been shown that RA is a high-affinity ligand(nanomolar range) for PPAR120573120575 activation in COS-7 cells[105] RA-mediated activation of PPAR120573120575 plays a role incell proliferation [106] In certain types of cells RA isrespectively delivered to RAR and PPAR120573120575 by cytosolretinoic acid-binding protein II (CRABP-II) and fatty acid-binding protein 5 [107] The activation of these two receptorsby RA has opposite effects on cell growth RA can activatePPAR120573120575 in preadipocytes and mature adipocytes [108 109]RA treatment prevents obesity development in diet-inducedobesity (DIO) via increase of lipolysis [108] and inhibition ofadipocyte differentiation [109]

However when human PPAR120573120575 was stably over-expressed in human keratinocyte cells no change inPPAR120573120575 target gene expression could be observed after thetreatment of RA [110] Many studies have shown that endo-cannabinoids regulate the activity of PPARs via direct andindirect mechanisms [111] The expression of endocannabi-noid receptor type 1 (CB1) is reduced upon overexpressionof PPAR120573120575 suggesting other pathways that PPAR120573120575 isinvolved in [112]

In summary retinol in hepatocytes can be either storedas REs or oxidized into retinal as shown in Figure 1 RA

6 ISRN Hepatology

HepatocyteCell membrane

RE Retinol Retinal RA

Other metabolic pathwaysNuclear

membrane

Cytosol RAOther ligands

RARRXR PPAR120573120575

COUP-TFII UpdownmRNAHNF4120572HNF4120572

RARE

Nucleus

Figure 1 The effects of RA production and other metabolicfactors on the activities of transcription factors associated with aretinoic acid-responsive element (RARE) in the promoter of anRA-targeted gene In primary hepatocytes RA is produced fromretinal derived from retinol Retinol can be esterified into retinylester (RE) or oxidized into retinal The RARE can be occupied byretinoic acid receptor (RAR) retinoid X receptor (RXR) hepatocytenuclear factor 4120572 (HNF4120572) chicken ovalbumin upstreampromoter-transcription factor II (COUP-TFII) and peroxisome proliferator-activated receptor 120573120575 (PPAR120573120575) in the forms of heterodimers orhomodimers These transcription factors receive signals from RAand metabolic pathways and regulate the expression of the RA-responsive gene

is dynamically produced and sent to nucleus where itinteracts with transcription factors associated with RAREin the enhancer regions of the RA-responsive genes Sofar the transcription factors that can be associated with aparticular RARE include RAR RXR COUP-TFII HNF4120572and PPAR120573120575 They form heterodimers or homodimers andbind to RARE to regulate the transcription rate of that geneThe nuclear receptors that occupy the RARE at any givenmoment may be determined by the VA status of the animaland the developmental differentiation and metabolic statesof hepatocytes These transcription factors integrate signalsfrom RA and other metabolic pathways to control the geneexpression positively and negatively Other metabolic signalsin combination with RA may affect the occupancy of thenuclear receptors bound to the RARE and their activationsand may in turn alter the outcomes of the RA-mediatedtranscription responses

2 VArsquos Roles in Glucose Metabolism

As a convenient energy source glucose can be used by all cellsthat are in charge of different physiological functionsGlucoseis metabolized differently in response to hormonal and nutri-tional statuses [113] Hepatocytes utilize and produce glucosedepending on the physiological needs and feeding status ofa subject These processes are regulated by nutritional andhormonal stimuli VA status has been implied to play a role

21 The Effects of VA Status on Hepatic Glycogen ContentsThe roles of VA in glucose metabolism had been suggestedIn 1937 the liver samples of patients who died of diabetesshowed an elevation of VA contents [114] When rats werefed a VA-deficient (VAD) diet to induce VA deficiency theirliver glycogen content was depleted [115] Since VA deficiencyalso caused reduction of food intake in the VAD rats a pair-feeding control group was included The pair-fed rats withequal energy intake as that of VAD rats had higher hepaticglycogen content [115] This depletion of hepatic glycogencontent was attributed to the reduction of glycogenesisfrom trioses rather than directly from glucose [115] Thephenomenon of the depletion of hepatic glycogen contentin the liver of VAD rats has also been observed recently inmy lab [116] On the other hand when rats were fed a dietwith excessive amounts of VA for two days an elevation ofthe hepatic glycogen content in the liver after fasting wasobserved [117] It seems that hepatic VA content is directlycorrelated with the hepatic glycogen content

22 The Effects of Animal VA Statuses and Retinoids onHepatic Gck Expression To initiate the hepatic glucose uti-lization glucose is phosphorylated into glucose 6-phosphateby hexokinases in the first reaction of glycolysis So far fourhexokinase isozymes hexokinase I (A) II (B) III (C) andIV (D) have been identified They have different tissue dis-tributions intracellular locations and kinetic characteristicsMammalian hexokinase IV (D) is also known as glucokinase(GK) (ATP d-hexose 6-phosphotransferase EC 2711) [118ndash121] Mutations of GK have been associated with MODY[122] GK has two unique features that differentiate it fromother hexokinase family members It has low affinity forglucose (higher Km) and it is insensitive to allosteric inhi-bition mediated by physiological concentrations of glucose6-phosphate whereas other hexokinases are sensitive to it[118 121 123 124] In addition to glucose other substrates ofGK include fructose mannose and 2-deoxyglucose [118]

Generally GK activity is mainly observed in the liverand pancreatic islets The 120573-cells and liver GK isoforms havesimilar kinetic properties [125 126] In the short term theGK activity can be regulated via allosteric interactions andcovalent modifications such as binding to GK regulatoryprotein [127] phosphorylation by protein kinase A [128] andinteractionwith a cytosolic GK-associated phosphatase [129]

The long-term regulation of GK activity is done throughthe transcription of its gene Gck which is differentiallyregulated by an upstream promoter in pancreatic 120573-cells anda downstream promoter in hepatocytes [130 131] Using astrain of transgenic mice containing the cDNA of humangrowth hormone gene driven by an upstream Gck promoterfragmentGck expression has been found in certain neuroen-docrine cells of the pancreas pituitary brain gut thyroidand lungs [132] Activation of the upstream or downstreampromoter leads to the generation of a Gck mRNA with aunique 51015840 sequence derived from exon 1120573 or 1L respectivelySince the translation initiation coden is located in the firstexon the GK proteins encoded by the different transcriptsdiffer in the first 15 amino acids at the amino terminus

ISRN Hepatology 7

[130 131] The mechanisms by which the upstream and thedownstream promoters are selectively activated in differentcells have not been revealedThe temporal and special controlof the promoter selectionmust be determined by signals fromdifferentiation and development processes

The upstream and downstream promoters are activatedbased on the hormonal and nutritional conditions of thesubject For example the hepatic but not the pancreatic 120573-cell Gck expression is reduced while fasting and increasedwhile refeeding [130] In the rat liver insulin and glucagonrespectively induce and inhibit the expression of GckmRNA[133ndash135] A long-standing question in the field is the insulin-responsive element (IRE) responsible for the insulin-inducedhepaticGck expression Using the reporter gene constructs tostudy insulin-induced Gck promoter activation has not beensuccessful For example a reporter gene construct containinga fragment of 55 kb hepatic Gck promoter failed to showany response to insulin treatment in rat primary hepatocytes[136] This suggests that the IRE of the hepatic Gck mightbe in an area not included in this 55 kb promoter fragmentAlternatively the unresponsiveness to insulin of the reportergene constructs in the experimental settings could be due tothe short-lived signal from insulin for Gck transcription aswe have shownpreviously [137] Interestingly the hepatocyte-specific enhancer region that controls the activation of liver-specific promoter has been located in the region from minus1003to minus707 relative to the transcription initiation site in primaryrat hepatocytes By contrast this region acts as a silencer inFTO-2B hepatoma cells and has no effects on insulinomacells [138] Further studies are needed to identify the insulin-responsive element in the hepatic Gck promoter

The direct effects of RA on the expression of Gck mRNAin primary rat hepatocytes have been studied Previouslyothers have shown that all-trans RA induced Gck expressionin primary rat hepatocytes However nonadditive effect ofRA on insulin-induced Gck expression was observed [139140] Recently we have shown that retinoids synergized withinsulin to induce Gck expression in primary rat hepatocytes[137] We have observed that all-trans retinol retinal and RAare able to synergize with insulin to induce Gck expressionprobably via the activation of RARRXR in primary rat hepa-tocytes In addition VA status also controls the expression ofhepatic Gck expression [137] The levels of Gck mRNA [116]and its activity [137] in the liver of VAD rats are lower thanthose of VA-sufficient (VAS) controls In addition a singletreatment of RA increases the hepatic Gck expression in rats[137]

23 The Effects of Animal VA Status and Retinoids onPck1 Gene Expression The plasma glucose homeostasis isachieved through its dietary intake and production fromendogenous noncarbohydrate sources During fasting glu-cose is generated via gluconeogenesis The cytosolic form ofphosphoenolpyruvate carboxykinase (PEPCK-C EC41132)which catalyzes the conversion of oxaloacetate into phos-phoenolpyruvate in the presence of GTP [141] has beenconsidered to be the first rate-limiting enzyme of gluconeoge-nesisThe expression of PEPCK-C gene (Pck1) and its activity

have been detected in the liver kidney adipose tissues andsome other tissues [141ndash143] Other than gluconeogenesisPEPCK-C activity has been considered to be responsible forglyceroneogenesis and cataplerosis [144] Since no allostericregulator of PEPCK-C has been identified its activity isprimarily controlled by the level of Pck1mRNA [141ndash143]

The transcription of hepatic Pck1 is regulated by hor-monal and nutritional stimuli In the liver fasting diabetescarbohydrate-free diets and high-fat diets increase Pck1 geneexpression whereas refeeding insulin treatment and high-carbohydrate diets decrease Pck1 gene expression Glucagonglucocorticoids thyroid hormone and RA induce hepaticPck1 expression while insulin and glucose inhibit it [145]

The transcription regulation of Pck1 has been studiedextensively [142 143] The protein-binding sites at the prox-imal region of rat Pck1 promoter have been determined byDNase I footprinting assays [146 147] Multiple regulatoryelements including distal proximal cyclic AMP-responsiveelement (CRE) [148] have been identified Proteins in ratliver nuclear extracts can interact with the two CREs andsix additional binding sites (P1 to 6) [142] The transcrip-tion factors that bind to these sites include HNF4120572 [149]glucocorticoid receptor [148 150ndash153] RAR [154ndash157] TR[154 158] LXR [159] COUP-TF [149] the Forkhead familyof transcription factors [160] CEBP and cAMP regulatoryelement-binding (CREB) protein [161] and SREBP-1c [162163] Additionally transcription coactivators such as CREB-binding protein (CBP) [164] steroid receptor coactivator 1(SRC1) [165] and peroxisome proliferator-activated receptorgamma coactivator-1-alpha (PGC-1120572) [166] also participatein the regulation of hepatic Pck1 gene expression

Using reporter gene assays and hepatoma cells twoRAREs have been identified in the hepatic Pck1 promoter[154 155 167]WhenPEPCKbovine growth hormone (bGH)transgenic mouse strains are used VA deficiency causes thereduction of the transgenersquos transcription [167]The RARE1 isconsidered to be important for mediating the RA-regulatedPck1 expression in the mouse liver [157] In mice VA statusaffects the association of RNApolymerase II and histone codeof Pck1 promoter [168 169] Later on these RAREs have beenshown to bind toHNF4120572 RXR120572 RAR120572 PPAR120572 and COUP-TFII [170]

In an attempt to study the lipophilic molecules that affectinsulin-regulated gene expression in primary rat hepatocyteswe have obtained lipophilic extract (LE) from the rat liverMyoriginal study has shown that this LE induces Pck1 expressionand attenuates insulin-mediated suppression of Pck1 tran-scription in primary rat hepatocytes [171] Interestingly thesame LE synergizes with insulin to induce Gck expression inthe same cells [137]The activemolecules in the LE are retinoland retinal [137] We have shown that retinol retinal andRA all can affect insulin-suppressed Pck1 expression [172]In rat primary hepatocytes the proximal one of the twoRAREs in the rat Pck1 promoter [154ndash156] is responsiblefor mediating the retinoid effects [172] The expression ofhepatic Pck1mRNA in rats seems to respond to VA deficiencydifferently from that in mice We have shown that the hepaticPck1mRNA level in the Zucker lean (ZL) rats is not reduced

8 ISRN Hepatology

Hepatocyte

Induction

Induction

Induction

1 2

Gck

Pck1

Cell membraneCytosol

RA RA

RARESynergy

Signalcascade Insulin

AttenuationNuclear

membrane NucleusRAREs

Inhibitio

n

Figure 2 RA synergizes with insulin to induce Gck expressionand attenuates insulin-suppressed Pck1 expression RA inducesthe expression levels of Gck and Pck1 via the activation of bothRARRXR (the oval dimmers on the RAREs) in the absenceof insulin Insulin alone stimulates the expression of Gck andsuppresses the expression of Pck1 In the presence of both insulinand RA the expression of Gck is further increased (synergy) Onthe other hand the insulin-mediated suppression of Pck1 expressionis attenuated This is because RA still induces Pck1 expressionvia activation of RAR in the presence of insulin Therefore Pck1transcript level in the RA + insulin group is higher than that in theinsulin group (attenuation)

in VA-deficient state [116] VA deficiency only reduces thehepatic Pck1mRNA in the Zucker fatty (ZF) rats [116]

It is important to note that the respective activities of GKand PEPCK-C are induced in different physiological condi-tions For example insulin induces Gck and suppresses Pck1expression as shown in Figure 2 In primary rat hepatocytesactivation of either RARs or RXRs by RA is sufficient toinduce the expression of both Pck1 [172] and Gck [137] How-ever activation of RAR potentiates (for the insulin-mediatedinduction of Gck expression) and attenuates (for the insulin-mediated suppression of Pck1 expression) insulin actionsat the same time in the same hepatocytes For Gck RA-mediated activation of RARs and RXRs can be potentiated byinsulin [137] which results in the synergy For Pck1 only RA-activated RXRs but not RARs are inhibited by insulin whichresults in the attenuation [172] This causes the production ofmore Pck1 mRNA in the presence of RA than in the absenceof it even in the insulin-suppressed state It indicates that themechanisms of RA-mediated activation of RARs and RXRsprobably depend on the promoter context or the isoformsassociated with the promoters of their downstream genesin the presence of insulin Therefore the roles of retinoidsin hepatic glucose metabolism deserve further investigationespecially the roles of the interactions between retinoidsand insulin signaling pathways in the regulation of genetranscription

24 Role of RBP4 in Insulin Resistance Plasma VA is boundto RBP4 which is mainly produced in the liver [13] TheRbp4 mRNA is also expressed to a certain extent in adipose

tissues and kidney [13] In the plasma retinol-RBP4 complexis associated with transthyretin (TTR) a process to increasethe size of the holo-RBP4-TTR complex to reduce the lossduring renal filtration [173]

Recently the plasma RBP4 has been suggested to playroles in metabolic homeostasis It has been reported thatinsulin-resistant human subjects and animals have higherplasma RBP4 levels than normal ones due to its elevatedproduction from adipose tissues [174] In mice RBP4administration has been shown to reduce insulin sensitivityand increase the expression levels of hepatic gluconeogenicgenes such as Pck1 and the catalytic subunit of glucose 6-phosphatase (G6pc) [175] Additionally reduction of plasmaretinol and RBP levels has been reported in type 1 diabeticpatients [176] and in streptozotocin- (STZ-) induced diabeticrats [177] Rbp4 knockout mice have improved insulin sen-sitivity [175] The treatment fenretinide a synthetic retinoidderivative that disrupts the association of RBP4 and TTRimproves insulin sensitivity in HFD-induced obese mice[175]

When a compound specifically developed to disrupt theRBP4 and TTR interaction was used to treat mice it suc-cessfully disrupted the formation of RBP4-TTR complex andcaused the reduction of plasma RBP4 level [178] Howeverthe reduction of plasma RBP4 level did not result in animprovement of insulin sensitivity [178] In addition theimprovement of insulin sensitivity in Rbp4 knockout micecould not be observed in this study [178] Therefore the ele-vation of insulin sensitivity in mice treated with fenretinideis probably due to a mechanism other than the disruption ofRBP-TTR complex and reduction of plasma RBP4 levels

3 Roles of VA in FA and TG Metabolism

FAs are needed for many aspects of cellular functions fromsignal transduction to energy production The continuoussurvival of a given cell depends on the constant energysupplies from the environment or storage sources Thestorage of FA in the form of TG ensures the constant energysupply in a cell or organism for a prolonged period oftime when environment energy is limited In animals thehomeostasis of FA and TG is dynamically regulated by theliver and the adipose tissues in response to nutritional andhormonal stimuli [179 180] During fasting or starvation FAsare released from adipose depots after lipolysis and oxidizedin the liver and muscle for energy production [181] Afterrefeeding dietary and newly synthesized FAs are convertedto TGs for the storage in the adipose tissues [182] On theother hand the altered regulation of this system may causeproblems For example the excessive synthesis and storage ofFAs in the form of TGs can cause the development of obesityand other metabolic diseases

31 The Effects of VA Status on the Body Fat and Plasma LipidProfile VA was first recognized as a dietary lipophilic factorwhich was essential to support the normal growth of labanimals [3 4] Subsequently it was observed that along withthe reduction of body mass the VAD rats that had been fed

ISRN Hepatology 9

aVADdiet at weaning (21 days old) formore than 9weeks hadreduction of carcass fat but not cholesterol content [183] Onthe other hand this reduction of body fat was not observedin the rats of the pair-feeding group which were given thesame amount of a VAS diet in weight and calories as theone consumed by the VAD rats [183] These results indicatethat the reduction of food intake alone could not be used toexplain the depletion of body fat in the VAD rats

The VA status also seems to affect the hepatic expressionof apo AI mRNA The expression of hepatic apo AI hasbeen shown to be sensitive to VA status [184] When theLewis strain rats develop VA deficiency the expression levelof hepatic but not intestinal apo AI mRNA is elevated Thisinduction is dropped upon single dosage of RA treatment[184] On the other hand in the intestine and liver of VA-deficient Wistar rats both all-trans RA and 9-cis RA caninduce apo AI mRNA levels [185] The same treatment canonly induce the mRNA level of apo CIII in the intestine butnot in the liver [185] In humans the plasma VA levels arepositively correlated with the elevations of proteins of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiapatients [186]

When male Wistar rats were fed a VAD diet for 3 monthsafter weaning (21 days old) they had lower plasma TGs andcholesterol levels than the control ones fed a VAS diet [187]When the hepatic synthesis of FAs and phospholipids wasanalyzed in the liver slices the incorporations of [14C]cholineinto phosphatidylcholine and [14C]acetate into FAs were alsoreduced in the VAD rats compared with their VAS controls[187] The VAD rats had lower activities and mRNA levels ofacetyl-CoA carboxylase but higher activity and mRNA levelof carnitine palmitoyltransferase-I than VAS rats had [187]These results demonstrate that there is a reduction of hepaticfatty acid synthesis along with an induction of hepatic fattyacid oxidation in the liver of VAD rats

My lab has conducted experiments and shown that VAstatus affects the obesity development in ZF rats and controlsplasma TG levels in ZL and ZF rats [116] ZF rats a ratmodel of obesity development [188] develop obesity dueto a missense mutation in the extracellular domain of allleptin receptor isoforms [189ndash191] They have been used forthe studies of obesity insulin resistance and other aspectsof metabolic diseases [192 193] We have analyzed growthplasma parameters and expression levels of hepatic genes ofmale ZL and ZF rats fed a VAD or a VAS diet at weaning(21 days of age) for 8 weeks Body masses of ZL and ZF ratsfed the VAD diet are lower than those of their correspondingcontrols fed the VAS diet at the end of the feeding periodThe VAD ZL or ZF rats begin to take less food than the VASones after five weeks on the diet The VAD ZL or ZF rats havelower plasma glucose TG insulin and leptin levels than theircorresponding VAS rats have The liver glycogen content netweights of epididymal fat and liver and fat-to-body massratio (ZL only) in the VAD rats are also lower than those inthe VAS ones [116] This demonstrates that VA status affectsplasma TG levels in both ZF and ZL rats and the obesitydevelopment in ZF rats This phenomenon may be caused by

the combination of VA deficiency and hypoinsulinemia sinceinsulin secretion is impaired in the VAD rats [194]

32 The Development of Hypertriglyceridemia inPatients Receiving Retinoic Acid-Based Treatments

321 The Uses of RA-Based Medicines in Clinic RA-basedmedicines tretinoin (all-trans RA) isotretinoin (13-cis RA)and alitretinoin (9-cis RA) have been used in clinic to treatdiseases such as acute promyelocytic leukemia and skindisorders [11] In fact isotretinoin has been widely used totreat severe acne Early clinical observations indicate that themedical use of isotretinoin in human subjects results in theelevation of their plasma TG levels [195ndash197] A significantportion of patients with acne receiving isotretinoin treatmentdeveloped hypertriglyceridemia [9 10] In addition thesystemic administration of isotretinoin in patients with acneresulted in the elevation of plasma levels of alanine amino-transferase (ALT) and aspartate aminotransferase (AST)indicating the liver damage [198]The hypertriglyceridemia isalso associated with reduced insulin sensitivity and elevatedTG in the very-low-density lipoprotein (VLDL) fraction[195] The treatment of all-trans RA resulted in body massgain and hypertriglyceridemia in patients with acute promye-locytic leukemia [199 200] Moreover RA treatment alsoraises plasma TG levels in rats [201ndash203]

322 The Mechanism of RA-Mediated Hypertriglyceridemiain Patients Apo CIII is produced from liver and consideredan inhibitor of LPL activity [204] Mice with Apoc3 geneknockout have hypotriglyceridemia and enhanced in vivoVLDL-TG clearance [205] On the other hand transgenicmice with overexpression of apo CIII develop hypertriglyc-eridemia [206] The RA-induced hypertriglyceridemia hasbeen attributed to RA-induced apo CIII expression

In healthy human subjects isotretinoin treatment causesa rise of plasma apo CIII protein level [207]This is caused bythe induction of Apoc3 mRNA via the activation of RXR ata RARE in its promoter [207] The plasma TG levels in ratstreated with RXR-specific agonist (LG100268) are inducedrapidly and constantly [208] This results in the reducedactivity of LPL in the heart and skeletal muscle of thoseanimals [208] The RARE is identified in the C3P regionwhich controls the hepatic specific expression of Apoc3 gene[75] Interestingly the same site is also considered to beresponsible for mediating the effects of HNF4120572 and COUP-TFII onApoc3 gene expression [209]The expression ofApoc3seems to be regulated differently by the C3P-binding proteins[75]

It is worth to note that insulin suppresses Apoc3 mRNAexpression in STZ-induced diabetic mice [210] In additionthe activation of RXR by LG100268 treatment induces insulinsensitivity and reduces TG levels in obese and diabetic mice[211] The understanding of the regulatory mechanism thatintegrates hormonal and nutritional signals at the regulatorysites such as C3P in Apoc3 promoter will shed some lightson the regulation of hepatic lipid homeostasis It will also

10 ISRN Hepatology

provide a novel target for the treatment of the RA-inducedhypertriglyeridemia

323 The Effects of RA Treatment on Obesity Developmentin Mice Interestingly the RA administration in rodentscauses reduction of body mass as summarized in [212] Thiskind of reduction of body mass has been associated withenhancement of insulin sensitivity in genetic [213] or DIOmice [108] The mechanisms of RA-mediated attenuation ofinsulin resistance have been thought to be the induction ofenergy expenditure through PPAR120573120575 activation [108] andthe inhibition of adipogenesis throughRXR120574 activation [109]On the other hand retinol can be metabolized in adipose tis-sues [214]Themice with deletion ofRaldh1 gene (Raldh1minusminus)have elevated retinal in their adipose tissues and are resistantto diet-induced obesity and insulin resistance [26] This hasbeen attributed to the suppression of adipogenesis by retinal-inhibited activation of PPAR120574 and RXR [26] It is interestingto note that either retinal or RA can inhibit the adipogenesisand cause the improvement of insulin sensitivity in micebased on these studies

33 Roles of VA and Retinoids in the Regulation of HepaticLipogenic Gene Expression Insulin resistance diabetes andother metabolic abnormalities are associated with profoundchanges of hepatic lipid and glucose metabolismThis can beattributed at least in part to the altered expression of genesinvolved in glucose and lipid metabolism [215] The hepaticlipogenesis contributes to the homeostasis of FAs and TGs

331 The Regulation of Hepatic Srebp-1c Expression by VAStatus and Retinoids Treatment Insulin plays an essentialrole in the hepatic FA synthesis It has been known for a whilethat insulin is needed for the glucose usage for lipogenesis andCO2production in the liver [216] The hepatic FA synthesis

rises sharply and continuously after rats are fasted and thenrefed a high-carbohydrate diet [217] The amount of fattyacid synthase (FAS) is induced in normal rats refed a high-carbohydrate diet after fasting and in STZ-induced diabeticrats after insulin administration [218] In the insulin-deficientrats the induction of FAS after refeeding occurs only wheninsulin injection is injected [219] a process attributed to theinduction of FAS gene (Fas) [220 221]

The transcription of hepatic Fas is controlled by a tran-scription factor named SREBP-1c [222] In the liver-specificSrebp-1c knockoutmouse liver the induction of Fas and otherlipogenic genes by refeeding after fasting is blunted [223]Interestingly insulin also specifically induces the Srebp-1cexpression in the liver [224] via two liver X receptor elements(LXREs) and one sterol-responsive element (SRE) [225]However in liver-specific insulin receptor knockoutmice theinduction of hepatic Srebp-1c by refeeding largely remainedunchanged [226] This suggests that nutrient-derived signalsmay activate downstream of insulin receptor signaling path-way to regulate Srebp-1c expression and hepatic lipogenesis[226]

As stated in the previous section my research group hasobserved that the VAD ZL and ZF rats have lower plasma TG

levels than their VAS controls [116] This is accompanied bythe reduction of the hepatic expression of Srebp-1cmRNA inVA-deficient animals [116] My research group has reportedfor the first time that retinoids synergize with insulin toinduce the expression of Srebp-1c in primary rat hepatocytes[227] Further analysis of the Srebp-1c promoter reveals thatthe previous identified LXREs responsible for mediatinginsulin-induced Srebp-1c expression are also RAREs [227]These observations show that retinoids (nutritional) andinsulin (hormonal) signals converge to regulate the FAsynthesis in the liver

332 The Effects of VA Catabolism on the Regulation of Srebp-1c Expression in Primary Rat Hepatocytes More recentlyretinoids have been proposed to play roles in glucose and lipidmetabolism and to maintain energy homeostasis [228 229]VA (retinol) is reversibly converted into retinal and retinalis irreversibly converted into RA [23] Retinal the precursorof RA production is able to synergize with insulin to inducethe Srebp-1c expression in primary rat hepatocytes [227]This suggests that the dynamic production of RA influencesthe expression of hepatic lipogenic genes It has led us toinvestigate the roles of RA production in the insulin-resistantanimals

In the liver of the Raldh1minusminus mice RA production isreduced in response to a load of retinol [230] The Raldh1minusminusmice are resistant to the development of obesity and insulinresistance after being fed an HFD [26] This is attributed tothe elevation of retinal content due to the lack of conversionof retinal to RA in the adipose tissues of the Raldh1minusminusmice Additionally the liver of the Raldh1minusminus mice hasaltered regulation of the genes for gluconeogenesis andsignificantly attenuated hepatic TG synthesis indicating theimportant role of hepatic VAmetabolism in glucose and lipidhomeostasis [231]

The hepatic expression levels of RALDH1 and RALDH2are induced in mice fed a high-cholesterol diet [232] SREsare located in the promoters of these two genes whichare induced by SREBP-1c overexpression The expression ofSrebp-1c is induced by the oxysterols derived from the high-cholesterol diet [232] This research work demonstrates theinteraction of cholesterol and RA metabolism in the liver Inaddition it has been shown that the level of Raldh1mRNA iselevated in the kidney of dbdb mice [233] Both dbdb miceand ZF rats develop obesity due to the mutation of leptinreceptor [234]

In an attempt to understand the roles of VA metabolismin the states of metabolic diseases we have compared theexpression levels of enzymes responsible for the productionof retinal and RA in the freshly isolated and cultured primaryhepatocytes from ZL rats and ZF rats [45] We have foundthat in the primary rat hepatocytes the enzymes responsiblefor the conversions of retinol to retinal and from retinal toRA are most likely RDH2 and RALDH1 respectively Theexpression levels of Raldh1 mRNA and its protein are higherin hepatocytes from ZF rats than in those from ZL rats[45] When overexpressed RALDH1 introduces the retinal-mediated induction of Srebp-1c in INS-1 cells which do not

ISRN Hepatology 11

respond to retinal in our previous study [227] These resultsindicate that insulin-resistant animals such as ZF rats mayhave alterations in retinoids metabolism

Thus we have hypothesized that the change of RAproduction from the oversupply of dietary VA due to thehyperphagia of ZF rats results in higher Srebp-1c expressionin ZF hepatocytes [45] The elevated SREBP-1c expressioncan further induceRaldh1 expression to create a feed-forwardmechanism that could be one of the reasons responsible forthe increased lipogenesis in the liver of ZF rats All of theseobservations indicate the potential roles of RA metabolismin the development of obesity and insulin resistance whichdeserves to be further studied

4 VArsquos Roles in Mediating Hepatic InsulinAction and Insulin Resistance

41 Insulin and Its Signal Transduction The insulin moleculeis made of two chains linked by one intra- and one interchaindisulfide bonds [235] The insulin receptor is a transmem-brane and heterotetramer tyrosine kinase receptor (two 120572and two 120573 subunits) linked by disulfide bonds as well [236]The binding of insulin to its receptor causes conformationchanges and transphosphorylation of the 120573-subunit tyrosinekinase [237 238] which initiates the signal transduction[239] Protein-protein interactions are involved in the trans-duction of insulin signalThe signal is transduced bymultiplecomponents in a complex network containing cascades ofkinases and phosphatases [240 241] The first intracellularcomponents mediating insulin signals are insulin recep-tor substrates (IRSs) protein molecules phosphorylated byinsulin receptor 120573-subunit and mediating insulin signals[242]

The insulin signal event is further amplified byphosphatidylinositide 3-kinases (PI3K)protein kinaseB (PKBAkt) pathway and GRB2mitogen-activated proteinkinase (MAPK) pathway [243ndash245] Another serinethre-onine kinase that can be activated by PI3K is the atypicalprotein kinase C [246] Human liver expresses severalprotein-tyrosine phosphatases (PTPs) [247] Okadai acid aninhibitor of protein phosphatase type 2A and type 1 inhibitsglycogen synthesis and insulin-stimulated Gck expression inprimary rat hepatocytes indicating that dephosphorylationmechanism may also participate in mediating insulinsignaling [248] These components are shared by insulin-likegrowth factor (IGF) receptor and involved in mediatinginsulin and IGF signals [249]

42 Metabolic Diseases and Insulin Resistance The rise ofthe number of people with one or more metabolic diseasessuch as obesity and diabetes in the world has become apublic health problem [250] The interactions of genetic andenvironmentalnutritional factors may be responsible for thecurrent rise of metabolic diseases The long evolutionaryprocess has equipped human and animal bodieswith a varietyof regulatory mechanisms controlling these interactions [251252] Human diets contain not only energy derived frommacronutrients but also micronutrients and other factors

which may influence the metabolic outcomes The roles ofindividual micronutrients in the development of metabolicdiseases are still unrevealed

One common property of human obesity and NIDDMis insulin resistance in which a given amount of insulinproduces less than normal physiological responses Dietaryfactors and manipulations have been considered to play arole in the development of insulin resistance in humans andanimals For example feeding an HFD to young and insulin-sensitive subjects for two days causes the development ofglucose intolerance [253] In the skeletal muscle of rats fedan HFD for 8 weeks the insulin-induced glucose uptakeis impaired [254] FFAs have been considered the factorsresponsible for HFD-induced leptin and insulin resistance[255ndash257]

43 Hepatic Insulin Resistance and Vicious Cycle The liverplays an essential role in the control of glucose andlipid homeostasis It coordinately regulates the processesin responses to nutritional and hormonal stimuli Insulinplays a major role in directing the liverrsquos metabolic status[258] which is partially attributed to the regulation of theexpression of genes involved in hepatic glucose and lipidmetabolism [215 259]

Insulin controls the expression of a variety of genesinvolved in glycolysis glycogenesis and lipogenesis andgluconeogenesis in the liver [145] Generally hepatic lipidand glucose metabolism is altered with the development ofinsulin resistance in obesity and NIDDM [258] This canbe reflected in the expression of insulin-regulated hepaticgenes for glucose and FA metabolism When the liver isinsulin sensitive insulin stimulates lipogenesis and inhibitsgluconeogenesis For example to regulate hepatic glucosehomeostasis insulin increases the expression of Gck gene[119 120] and Srebp-1c [224] a family member of SREBPswhich regulate the hepatic cholesterol and FA biosynthesisand their homeostasis [260] It suppresses the expressionof Pck1 [142] and G6pc [145] which control the first andlast steps of gluconeogenesis respectively When the liver isinsulin resistant insulin no longer inhibits gluconeogenesisHowever the liver still keeps the elevated lipogenesis Theelevated FA biosynthesis in the insulin-resistant state furtherfacilitates insulin secretion from pancreatic 120573-cells whichprobably enhances lipogenesis and results in a vicious cycle[113 261] The coexistence of the hepatic insulin resistanceand sensitivity at the gene expression level has been observedin rodent obese and diabetic models [215 258] Howeverthe mechanism of this coexistence of insulin sensitivity andresistance has not been revealed [261]

Recently the SREBP cleavage-activating protein gene(Scap) an escort protein necessary for generating nuclearforms of SREBPs has been knocked out in insulin-resistantobob mice [262] Deficiency of hepatic Scap reverses liverlipogenesis and steatosis in obobmice However the plasmalevels of glucose and insulin and the hepatic expression levelsof Pck1 andG6pcwere not different between the control obobmice and the obob mice with liver-specific Scap knockout[262] It seems that the suppression of hepatic FA synthesis

12 ISRN Hepatology

is not sufficient to correct insulin resistance Whether otherfactors play a role in the hepatic insulin resistance is still anopen question

The clinical use of RA-based medicine such asisotretinoin (13-cis RA) caused elevation of plasma TGlevels in human subjects [195ndash197] This increase in plasmaTG levels is also observed in rats [201ndash203] From our VAstatus studies we have shown that VA status affected theobesity development in ZF rats and reduced plasma insulinand TG levels in ZL and ZF rats suggesting improvement ofinsulin sensitivity [116] The hepatic expression of Srebp-1cwas reduced in VA-deficient animals [116] RA synergizeswith insulin to induce the expression of Srebp-1c in primaryrat hepatocytes [227] On the other hand RA treatmentinduces Pck1 expression and attenuates insulin-mediatedsuppression of its expression in primary rat hepatocytes [172]All of these observations demonstrate that RA attenuatesinsulin action (insulin-suppressed Pck1 expression) andstill promotes insulin action (insulin-induced Srebp-1cexpression) in the same primary hepatocytes

44 Possible Mechanism by Which RA Production Causes theDevelopment of the Vicious Cycle in Hepatocytes Could RAor other metabolites from VA catabolism be a factor thatcontributes to the hepatic insulin resistance and the viciouscycleUsing the regulation ofPck1 and Srebp-1c as themodel Ihave come upwith the following scheme to show that retinoidmetabolism could be a factor that causes the vicious cycle inthe liver As shown in Figure 3(a) in insulin-sensitive hepa-tocytes RA derived from retinal coordinates with insulin toregulate the expression of Srebp-1c and Pck1 The SREBP-1cprotein is processed to mature form a step that can be facili-tated by insulin [263] The mature form of SREBP-1c entersinto the nucleus and induces the mRNA levels of Raldh1and Fas which are respectively transcribed into RALDH1and FAS RALDH1 catalyzes the conversion of retinal to RAFAS catalyzes the synthesis of palmitate which is esterifiedinto TGs or elongated to longer FAs The Pck1 mRNA isused to translate into PEPCK-C protein which contributesto glucogenogenesis In the insulin-resistant hepatocytes asshown in Figure 3(b) the elevation of Raldh1 expressiondue to leptin deficiency [45] or induction of SREBP-1c byhigh-cholesterol feeding [232] induces the production of RAThe elevated RA levels will stimulate the transcription ofSrebp-1c and Pck1 This leads to more production of SREBP-1c and its mature form in the presence of higher insulinlevels in the insulin-resistant state The induction of SREBP-1c further enhances the transcription of Raldh1 and Fas andtheir corresponding proteins for the production of moreRAs and FAs respectively The RA production and SREBP-1c expression form a feed-forward cycle which causes moreTG and RA production in the insulin-resistant liver At thesame time more of the PEPCK-C protein is generated dueto the elevated Pck1 transcription by RA stimulation whichis not responsive to insulin inhibition as we have shown in[172] This leads to elevated gluconeogenesis in the insulin-resistant liver Eventually the phenotypes appear as if insulin

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1cRetinal

RALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(a) Insulin-sensitive hepatocytes

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1c

RetinalRALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(b) Insulin-resistant hepatocytes

Figure 3 The effects of RA on the insulin-regulated Srebp-1cand Pck1 expression levels the protein levels of SREBP-1c theexpression levels of Raldh1 and Fas and the fatty acid synthesisand gluconeogenesis in insulin-sensitive (a) and insulin-resistant (b)hepatocytes Please see the text in this paper for description Uparrows next to the text indicate induction The intensified weight ofthe lines indicates the induction of that part of the pathway

no longer suppresses gluconeogenesis while it still stimulatesFA synthesis in the insulin-resistant state

5 Perspectives and Future Directions

I have proposed a mechanism by which VA metabolismcontributes to the development of hepatic insulin resistanceIt explains some observations reported in the previous studiesof rodent obese and diabetic models [215 258] However itleavesmore open questionsThefirst one iswhat the initiationfactor is So far the elevated expression of Raldh1 mRNA inthe liver has been observed in ZF rats [45] and mice fed ahigh-cholesterol diet [232] These two conditions cause a lotof physiological changes such as overfeeding in ZF rats andchange of cholesterol biosynthesis in response to the feedingof high-cholesterol diet Knocking down Raldh1 specificallyin hepatocytes is needed to answer these questions The

ISRN Hepatology 13

second question is whether RA synthesis in hepatocytesis a regulated process in response to dietary or hormonalstimulations If Raldh1 is a downstream gene of SREBP-1cit should be regulated when the SREBP-1c level changes Asthe expression of Srebp-1c responds to insulin stimulation andoxysterols the regulation of Raldh1 expression in the livershould be studied The third question is why it is RALDH1but not other RALDHs Specific inhibitors of RALDHsmay be needed to answer this question Last question iswhether we can attenuate insulin resistance by suppressingthe RALDH1 activity in the liver It has been shown thatRaldh1minusminus mice are still insulin sensitive when they are onan HFD [26] This has been attributed to the effects on theadipogenesis However the liver of those knockout mice hasreduced lipid synthesis [231] Further studies are warrantedto answer all of these questions Hopefully it can become anintervention point for the treatment of insulin resistance andmetabolic diseases

Acknowledgments

This work was financially supported by a research grantfrom Allen Foundation Inc (to Guoxun Chen) a start-up fund from the University of Tennessee at Knoxville (toGuoxun Chen) and a Scientist Development Grant fromthe AmericanHeart Association (09SDG2140003 to GuoxunChen) The author thanks his colleague Dr Lauren Gellar forreading through this paper and offering her edits

References

[1] F G Hopkins ldquoFeeding experiments illustrating the impor-tance of accessory factors in normal dietariesrdquo The Journal ofPhysiology vol 44 no 5-6 pp 425ndash460 1912

[2] K J Carpenter ldquoA short history of nutritional science part 3(1912ndash1944)rdquo Journal of Nutrition vol 133 no 10 pp 3023ndash30322003

[3] E V McCollum and M Davis ldquoThe necessity of certain lipinsin the diet during growthrdquo Journal of Biological Chemistry vol15 no 1 pp 167ndash175 1913

[4] T B Osborne and L B Mendel ldquoFeeding experiments with fat-free food mixturesrdquo Journal of Biological Chemistry vol 12 no1 pp 81ndash89 1912

[5] R D Semba ldquoOn the lsquoDiscoveryrsquo of Vitamin Ardquo Annals ofNutrition and Metabolism vol 61 no 3 pp 192ndash198 2012

[6] R Blomhoff and H K Blomhoff ldquoOverview of retinoidmetabolism and functionrdquo Journal of Neurobiology vol 66 no7 pp 606ndash630 2006

[7] A Sommer ldquoVitamin A deficiency and clinical disease anhistorical overviewrdquo Journal of Nutrition vol 138 no 10 pp1835ndash1839 2008

[8] K J Rothman L L Moore M R Singer U-S Nguyen SMannino and A Milunsky ldquoTeratogenicity of high vitamin Aintakerdquo The New England Journal of Medicine vol 333 no 21pp 1369ndash1373 1995

[9] S Bershad A Rubinstein and J R Paterniti Jr ldquoChanges inplasma lipids and lipoproteins during isotretinoin therapy foracnerdquoThe New England Journal of Medicine vol 313 no 16 pp981ndash985 1985

[10] N Rodondi R Darioli A-A Ramelet et al ldquoHigh risk forhyperlipidemia and the metabolic syndrome after an episodeof hypertriglyceridemia during 13-cis retinoic acid therapy foracne a pharmacogenetic studyrdquo Annals of Internal Medicinevol 136 no 8 pp 582ndash589 2002

[11] H-U Klor A Weizel M Augustin et al ldquoThe impact oforal vitamin A derivatives on lipid metabolism what recom-mendations can be derived for dealing with this issue in thedaily dermatological practicerdquo Journal of the German Societyof Dermatology vol 9 no 8 pp 600ndash607 2011

[12] R M Russell ldquoThe vitamin A spectrum from deficiency totoxicityrdquoThe American Journal of Clinical Nutrition vol 71 no4 pp 878ndash884 2000

[13] A C Ross B Caballero R J Cousins K L Tucker and T RZiegler Modern Nutrition in Health and Diseases 11th edition2012

[14] E H Harrison ldquoMechanisms of digestion and absorption ofdietary vitamin Ardquo Annual Review of Nutrition vol 25 no 1pp 87ndash103 2005

[15] M R Lakshman ldquoAlpha and omega of carotenoid cleavagerdquoJournal of Nutrition vol 134 no 1 pp 241ndash245 2004

[16] I Potrykus ldquoNutritionally enhanced rice to combat malnutri-tion disorders of the poorrdquo Nutrition Reviews vol 61 no 6 ppS101ndashS104 2003

[17] A Wyss ldquoCarotene oxygenases a new family of double bondcleavage enzymesrdquo Journal of Nutrition vol 134 no 1 pp 246ndash250 2004

[18] R Kawaguchi J Yu J Honda et al ldquoA membrane receptor forretinol binding protein mediates cellular uptake of vitamin ArdquoScience vol 315 no 5813 pp 820ndash825 2007

[19] P Alapatt F Guo S M Komanetsky et al ldquoLiver retinoltransporter and receptor for serum retinol-binding protein(RBP4)rdquo Journal of Biological Chemistry vol 288 no 2 pp1250ndash1265 2013

[20] A R Moise N Noy K Palczewski and W S Blaner ldquoDeliveryof retinoid-based therapies to target tissuesrdquo Biochemistry vol46 no 15 pp 4449ndash4458 2007

[21] G Duester ldquoFamilies of retinoid dehydrogenases regulatingvitamin A function Production of visual pigment and retinoicacidrdquo European Journal of Biochemistry vol 267 no 14 pp4315ndash4324 2000

[22] M Theodosiou V Laudet and M Schubert ldquoFrom carrotto clinic an overview of the retinoic acid signaling pathwayrdquoCellular andMolecular Life Sciences vol 67 no 9 pp 1423ndash14452010

[23] J L Napoli ldquoInteractions of retinoid binding proteins andenzymes in retinoidmetabolismrdquoBiochimica et BiophysicaActavol 1440 no 2-3 pp 139ndash162 1999

[24] X Chai M H E M Boerman Y Zhai and J L NapolildquoCloning of a cDNA for liver microsomal retinol dehydro-genase A tissue-specific short-chain alcohol dehydrogenaserdquoJournal of Biological Chemistry vol 270 no 8 pp 3900ndash39041995

[25] B X Wu G Moiseyev Y Chen B Rohrer R K Crouch andJ-XMa ldquoIdentification of RDH10 an all-trans retinol dehydro-genase in retinal Muller cellsrdquo Investigative Ophthalmology andVisual Science vol 45 no 11 pp 3857ndash3862 2004

[26] O Ziouzenkova G Orasanu M Sharlach et al ldquoRetinalde-hyde represses adipogenesis and diet-induced obesityrdquo NatureMedicine vol 13 no 6 pp 695ndash702 2007

14 ISRN Hepatology

[27] J L Napoli ldquoPhysiological insights into all-trans-retinoic acidbiosynthesisrdquo Biochimica et Biophysica Acta vol 1821 no 1 pp152ndash167 2012

[28] G Wolf ldquoTissue-specific increases in endogenous all-transretinoic acid possible contributing factor in ethanol toxicityrdquoNutrition Reviews vol 68 no 11 pp 689ndash692 2010

[29] P V Bhat J Labrecque JM Boutin A Lacroix andA YoshidaldquoCloning of a cDNA encoding rat aldehyde dehydrogenase withhigh activity for retinal oxidationrdquoGene vol 166 no 2 pp 303ndash306 1995

[30] M Lin M Zhang M Abraham S M Smith and J LNapoli ldquoMouse retinal dehydrogenase 4 (RALDH4) molecularcloning cellular expression and activity in 9-cis-retinoic acidbiosynthesis in intact cellsrdquo Journal of Biological Chemistry vol278 no 11 pp 9856ndash9861 2003

[31] F A Mic A Molotkov X Fan A E Cuenca and GDuester ldquoRALDH3 a retinaldehyde dehydrogenase that gener-ates retinoic acid is expressed in the ventral retina otic vesicleand olfactory pit during mouse developmentrdquo Mechanisms ofDevelopment vol 97 no 1-2 pp 227ndash230 2000

[32] X Wang P Penzes and J L Napoli ldquoCloning of a cDNAencoding an aldehyde dehydrogenase and its expression inEscherichia coli recognition of retinal as substraterdquo Journal ofBiological Chemistry vol 271 no 27 pp 16288ndash16293 1996

[33] A Molotkov and G Duester ldquoGenetic evidence that retinalde-hyde dehydrogenase Raldh1 (Aldh1a1) functions downstreamof alcohol dehydrogenase Adh1 in metabolism of retinol toretinoic acidrdquo Journal of Biological Chemistry vol 278 no 38pp 36085ndash36090 2003

[34] G Elizondo J Corchero E Sterneck and F J GonzalezldquoFeedback inhibition of the retinaldehyde dehydrogenase geneALDH1 by retinoic acid through retinoic acid receptor 120572and CCAATenhancer-binding protein 120573rdquo Journal of BiologicalChemistry vol 275 no 50 pp 39747ndash39753 2000

[35] G Elizondo I M Medina-Dıaz R Cruz F J Gonzalez and LVega ldquoRetinoic acid modulates retinaldehyde dehydrogenase 1gene expression through the induction of GADD153-CEBP120573interactionrdquo Biochemical Pharmacology vol 77 no 2 pp 248ndash257 2009

[36] K Fujiwara M Kikuchi K Horiguchi et al ldquoEstrogen receptoralpha regulates retinaldehyde dehydrogenase 1 expression in ratanterior pituitary cellsrdquo Endocrine Journal vol 56 no 8 pp963ndash973 2009

[37] K Fujiwara F Maekawa M Kikuchi S Takigami T Yadaand T Yashiro ldquoExpression of retinaldehyde dehydrogenase(RALDH)2 and RALDH3 but not RALDH1 in the developinganterior pituitary glands of ratsrdquo Cell and Tissue Research vol328 no 1 pp 129ndash135 2007

[38] GWolf ldquoThe enzymatic cleavage of 120573-carotene still controver-sialrdquo Nutrition Reviews vol 53 no 5 pp 134ndash137 1995

[39] S Abu-Abed P Dolle D Metzger B Beckett P Chambonand M Petkovich ldquoThe retinoic acid-metabolizing enzymeCYP26A1 is essential for normal hindbrain patterning verte-bral identity and development of posterior structuresrdquo Genesand Development vol 15 no 2 pp 226ndash240 2001

[40] M A Leo S Iida and C S Lieber ldquoRetinoic acid metabolismby a system reconstituted with cytochrome P-450rdquo Archives ofBiochemistry and Biophysics vol 234 no 1 pp 305ndash312 1984

[41] MA Leo JM Lasker J L Raucy C-I KimM Black andC SLieber ldquoMetabolism of retinol and retinoic acid by human livercytochrome P450IIC8rdquoArchives of Biochemistry and Biophysicsvol 269 no 1 pp 305ndash312 1989

[42] R Quere A Baudet B Cassinat et al ldquoPharmacogenomicanalysis of acute promyelocytic leukemia cells highlightsCYP26cytochrome metabolism in differential all-trans retinoic acidsensitivityrdquo Blood vol 109 no 10 pp 4450ndash4460 2007

[43] J AWhite B Beckett-Jones Y-D Guo et al ldquocDNA cloning ofhuman retinoic acid-metabolizing enzyme (hP450RAI) identi-fies a novel family of cytochromes p450 (CYP26)rdquo Journal ofBiological Chemistry vol 272 no 30 pp 18538ndash18541 1997

[44] Y Zhang R Zolfaghari Reza and A C Ross ldquoMultiple retinoicacid response elements cooperate to enhance the inducibility ofCYP26A1 gene expression in liverrdquo Gene vol 464 no 1-2 pp32ndash43 2010

[45] Y Li Y Zhang R Li et al ldquoThe hepatic raldh1 expression iselevated in Zucker fatty rats and its over-expression introducedthe retinal-induced Srebp-1c expression in INS-1 cellsrdquo PLoSONE vol 7 no 9 Article ID e45210 2012

[46] R M Evans ldquoThe nuclear receptor superfamily a Rosetta stonefor physiologyrdquo Molecular Endocrinology vol 19 no 6 pp1429ndash1438 2005

[47] P Chambon ldquoA decade of molecular biology of retinoic acidreceptorsrdquo FASEB Journal vol 10 no 9 pp 940ndash954 1996

[48] D J Mangelsdorf and RM Evans ldquoThe RXR heterodimers andorphan receptorsrdquo Cell vol 83 no 6 pp 841ndash850 1995

[49] J E Balmer and R Blomhoff ldquoA robust characterization ofretinoic acid response elements based on a comparison of sitesin three speciesrdquo Journal of Steroid Biochemistry and MolecularBiology vol 96 no 5 pp 347ndash354 2005

[50] R Kurokawa J DiRenzo M Boehm et al ldquoRegulation ofretinoid signalling by receptor polarity and allosteric control ofligand bindingrdquo Nature vol 371 no 6497 pp 528ndash531 1994

[51] A Cvekl and W-L Wang ldquoRetinoic acid signaling in mam-malian eye developmentrdquo Experimental Eye Research vol 89no 3 pp 280ndash291 2009

[52] V Dupe M Davenne J Brocard et al ldquoIn vivo functional anal-ysis of the Hoxa-1 31015840 retinoic acid response element (31015840RARE)rdquoDevelopment vol 124 no 2 pp 399ndash410 1997

[53] A C Ross ldquoRetinoid production and catabolism role of dietin regulating retinol esterification and retinoic acid oxidationrdquoJournal of Nutrition vol 133 no 1 pp 291ndash296 2003

[54] T Moore and P D Holmes ldquoThe production of experimentalvitamin A deficiency in rats andmicerdquo Laboratory Animals vol5 no 2 pp 239ndash250 1971

[55] A C Ross and E H Harrison ldquoVitamin A and carotenoidsrdquoin Handbook of Vitamins D E McCormick R R Rucker J WSuttie et al Eds CRC Press Boca Raton Fla USA 4th edition2006

[56] A Chawta J J Repa R M Evans and D J MangelsdorfldquoNuclear receptors and lipid physiology opening the x-filesrdquoScience vol 294 no 5548 pp 1866ndash1870 2001

[57] C K Glass and M G Rosenfeld ldquoThe coregulator exchangein transcriptional functions of nuclear receptorsrdquo Genes andDevelopment vol 14 no 2 pp 121ndash141 2000

[58] A L Bookout Y Jeong M Downes R T Yu R M EvansandD JMangelsdorf ldquoAnatomical profiling of nuclear receptorexpression reveals a hierarchical transcriptional networkrdquo Cellvol 126 no 4 pp 789ndash799 2006

[59] B Mascrez M Mark W Krezel et al ldquoDifferential contribu-tions of AF-1 andAF-2 activities to the developmental functionsof RXR120572rdquo Development vol 128 no 11 pp 2049ndash2062 2001

[60] D Li T Li F Wang H Tian and H H Samuels ldquoFunctionalevidence for retinoid X receptor (RXR) as a nonsilent partner

ISRN Hepatology 15

in the thyroid hormone receptorRXR heterodimerrdquoMolecularand Cellular Biology vol 22 no 16 pp 5782ndash5792 2002

[61] F M Sladek W Zhong E Lai and J E Darnell Jr ldquoLiver-enriched transcription factor HNF-4 is a novel member ofthe steroid hormone receptor superfamilyrdquo Genes and Develop-ment vol 4 no 12 pp 2353ndash2365 1990

[62] K Yamagata H Furuta N Oda et al ldquoMutations in thehepatocyte nuclear factor-4120572 gene inmaturity-onset diabetes ofthe young (MODY1)rdquo Nature vol 384 no 6608 pp 458ndash4601996

[63] M Stoffel and S ADuncan ldquoThematurity-onset diabetes of theyoung (MODY1) transcription factor HNF4120572 regulates expres-sion of genes required for glucose transport and metabolismrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 24 pp 13209ndash13214 1997

[64] M Lehto P-O Bitzen B Isomaa et al ldquoMutation in the HNF-4120572 gene affects insulin secretion and triglyceride metabolismrdquoDiabetes vol 48 no 2 pp 423ndash425 1999

[65] G P Hayhurst Y-H Lee G Lambert J M Ward and F JGonzalez ldquoHepatocyte nuclear factor 4120572 (Nuclear receptor 2A1)is essential formaintenance of hepatic gene expression and lipidhomeostasisrdquo Molecular and Cellular Biology vol 21 no 4 pp1393ndash1403 2001

[66] U Roth K Jungermann and T Kietzmann ldquoActivation ofglucokinase gene expression by hepatic nuclear factor 4120572 inprimary hepatocytesrdquo Biochemical Journal vol 365 no 1 pp223ndash228 2002

[67] S Mandard R Stienstra P Escher et al ldquoGlycogen synthase2 is a novel target gene of peroxisome proliferator-activatedreceptorsrdquo Cellular and Molecular Life Sciences vol 64 no 9pp 1145ndash1157 2007

[68] F Rajas A Gautier I Bady S Montano and G MithieuxldquoPolyunsaturated fatty acyl coenzyme a suppress the glucose-6-phosphatase promoter activity bymodulating the DNA bindingof hepatocyte nuclear factor 4120572rdquo Journal of Biological Chemistryvol 277 no 18 pp 15736ndash15744 2002

[69] B Viollet A Kahn and M Raymondjean ldquoProtein kinase A-dependent phosphorylation modulates DNA-binding activityof hepatocyte nuclear factor 4rdquoMolecular and Cellular Biologyvol 17 no 8 pp 4208ndash4219 1997

[70] L Palanker J M Tennessen G Lam and C S Thum-mel ldquoDrosophila HNF4 regulates lipid mobilization and 120573-oxidationrdquo Cell Metabolism vol 9 no 3 pp 228ndash239 2009

[71] A Miura K Yamagata M Kakei et al ldquoHepatocyte nuclearfactor-4120572 is essential for glucose-stimulated insulin secretion bypancreatic 120573-cellsrdquo Journal of Biological Chemistry vol 281 no8 pp 5246ndash5257 2006

[72] R Bartoov-Shifman R Hertz H Wang C B Wollheim JBar-Tana and M D Walker ldquoActivation of the insulin genepromoter through a direct effect of hepatocyte nuclear factor4120572rdquo Journal of Biological Chemistry vol 277 no 29 pp 25914ndash25919 2002

[73] H Wang P Maechler P A Antinozzi K A Hagenfeldt andC B Wollheim ldquoHepatocyte nuclear factor 4120572 regulates theexpression of pancreatic 120573-cell genes implicated in glucosemetabolism and nutrient-induced insulin secretionrdquo Journal ofBiological Chemistry vol 275 no 46 pp 35953ndash35959 2000

[74] K Reue T Leff and J L Breslow ldquoHuman apolipoproteinCIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factorsrdquo Journal ofBiological Chemistry vol 263 no 14 pp 6857ndash6864 1988

[75] T Leff K Reue A Melian H Culver and J L BreslowldquoA regulatory element in the apoCIII promoter that directshepatic specific transcription binds to proteins in expressingand nonexpressing cell typesrdquo Journal of Biological Chemistryvol 264 no 27 pp 16132ndash16137 1989

[76] S N Lavrentiadou M Hadzopoulou-Cladaras D Kardassisand V I Zannis ldquoBinding specificity and modulation of thehuman apocIII promoter activity by heterodimers of ligand-dependent nuclear receptorsrdquo Biochemistry vol 38 no 3 pp964ndash975 1999

[77] T R Magee Y Cai M E El-Houseini J Locker and Y-JY Wan ldquoRetinoic acid mediates down-regulation of the 120572-fetoprotein gene through decreased expression of hepatocytenuclear factorsrdquo Journal of Biological Chemistry vol 273 no 45pp 30024ndash30032 1998

[78] A Qian Y Cai T R Magee and Y J Y Wan ldquoIdentificationof retinoic acid-responsive elements on the HNF1alpha andHNF4alpha genesrdquo Biochemical and Biophysical Research Com-munications vol 276 no 3 pp 837ndash842 2000

[79] H Nakshatri and P Chambon ldquoThe directly repeatedRG(GT)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites forRAR RXR HNF-4 and ARP-1 homo- and heterodimersrdquoJournal of Biological Chemistry vol 269 no 2 pp 890ndash9021994

[80] T Makita G Hernandez-Hoyos T H-P Chen H Wu E VRothenberg and H M Sucov ldquoA developmental transition indefinitive erythropoiesis erythropoietin expression is sequen-tially regulated by retinoic acid receptors andHNF4rdquoGenes andDevelopment vol 15 no 7 pp 889ndash901 2001

[81] T I Kambe J Tada-Kambe Y Kuge Y Yamaguchi-Iwai MNagao and R Sasaki ldquoRetinoic acid stimulates erythropoietingene transcription in embryonal carcinoma cells through thedirect repeat of a steroidthyroid hormone receptor responseelement half-site in the hypoxia-response enhancerrdquo Blood vol96 no 9 pp 3265ndash3271 2000

[82] F-J Lin J Qin K Tang S Y Tsai and M-J Tsai ldquoCoup drsquoEtatan orphan takes controlrdquo Endocrine Reviews vol 32 no 3 pp404ndash421 2011

[83] L-H Wang S Y Tsai R G Cook W G Beattie M-J Tsaiand BW OrsquoMalley ldquoCOUP transcription factor is a member ofthe steroid receptor superfamilyrdquoNature vol 340 no 6229 pp163ndash166 1989

[84] X Leng A J Cooney S Y Tsai and M-J Tsai ldquoMolecularmechanisms of COUP-TF-mediated transcriptional repressionevidence for transrepression and active repressionrdquo Molecularand Cellular Biology vol 16 no 5 pp 2332ndash2340 1996

[85] L Li X Xie J Qin et al ldquoThe nuclear orphan receptorCOUP-TFII plays an essential role in adipogenesis glucosehomeostasis and energy metabolismrdquo Cell Metabolism vol 9no 1 pp 77ndash87 2009

[86] F A Pereira Q Yuhong G Zhou M-J Tsai and S YTsai ldquoThe orphan nuclear receptor COUP-TFII is required forangiogenesis and heart developmentrdquo Genes and Developmentvol 13 no 8 pp 1037ndash1049 1999

[87] N Takamoto I Kurihara K Lee F J DeMayo M-J Tsai andS Y Tsai ldquoHaploinsufficiency of chicken ovalbumin upstreampromoter transcription factor II in female reproductionrdquoMolec-ular Endocrinology vol 19 no 9 pp 2299ndash2308 2005

[88] P Zhang M Bennoun C Gogard et al ldquoExpression of COUP-TFII in metabolic tissues during developmentrdquo Mechanisms ofDevelopment vol 119 no 1 pp 109ndash114 2002

16 ISRN Hepatology

[89] Z Xu S Yu C-H Hsu J Eguchi and E D Rosen ldquoTheorphan nuclear receptor chicken ovalbumin upstream pro-moter-transcription factor II is a critical regulator of adipogene-sisrdquoProceedings of theNationalAcademy of Sciences of theUnitedStates of America vol 105 no 7 pp 2421ndash2426 2008

[90] P Bardoux P Zhang D Flamez et al ldquoEssential role of chickenovalbumin upstreampromoter-transcription factor II in insulinsecretion and insulin sensitivity revealed by conditional geneknockoutrdquo Diabetes vol 54 no 5 pp 1357ndash1363 2005

[91] G Achatz B Holzl R Speckmayer C Hauser F Sandhoferand B Paulweber ldquoFunctional domains of the human orphanreceptor ARP-1COUP-TFII involved in active repression andtransrepressionrdquo Molecular and Cellular Biology vol 17 no 9pp 4914ndash4932 1997

[92] S A Kliewer K Umesono R A Heyman D J MangelsdorfJ A Dyck and R M Evans ldquoRetinoid X receptor-COUP-TFinteractionsmodulate retinoic acid signalingrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol89 no 4 pp 1448ndash1452 1992

[93] A J Cooney S Y Tsai BW OrsquoMalley andM-J Tsai ldquoChickenovalbumin upstreampromoter transcription factor (COUP-TF)dimers bind to different GGTCA response elements allowingCOUP-TF to repress hormonal induction of the vitamin D3thyroid hormone and retinoic acid receptorsrdquo Molecular andCellular Biology vol 12 no 9 pp 4153ndash4163 1992

[94] SW Kruse K Suino-Powell X E Zhou et al ldquoIdentification ofCOUP-TFII orphannuclear receptor as a retinoic acid-activatedreceptorrdquo PLoS Biology vol 6 no 9 Article ID e227 2008

[95] J P Berger T E Akiyama and P T Meinke ldquoPPARs thera-peutic targets for metabolic diseaserdquo Trends in PharmacologicalSciences vol 26 no 5 pp 244ndash251 2005

[96] JM Peters andF J Gonzalez ldquoSorting out the functional role(s)of peroxisome proliferator-activated receptor-120573120575 (PPAR120573120575)in cell proliferation and cancerrdquo Biochimica et Biophysica Actavol 1796 no 2 pp 230ndash241 2009

[97] A Tenenbaum and E Fisman ldquoBalanced pan-PPAR activatorbezafibrate in combination with statin comprehensive lipidscontrol and diabetes preventionrdquo Cardiovascular Diabetologyvol 11 no 1 article 140 2012

[98] O Braissant F Foufelle C Scotto M Dauca and W WahlildquoDifferential expression of peroxisome proliferator-activatedreceptors (PPARs) tissue distribution of PPAR-120572 -120573 and -120574 inthe adult ratrdquo Endocrinology vol 137 no 1 pp 354ndash366 1996

[99] H Higashiyama A N Billin Y Okamoto M Kinoshita andS Asano ldquoExpression profiling of Peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues usingtissue microarrayrdquo Histochemistry and Cell Biology vol 127 no5 pp 485ndash494 2007

[100] P S Jones R Savory P Barratt et al ldquoChromosomal local-isation inducibility tissue-specific expression and strain dif-ferences in three murine peroxisome-proliferator-activated-receptor genesrdquo European Journal of Biochemistry vol 233 no1 pp 219ndash226 1995

[101] S A Kliewer B M Forman B Blumberg et al ldquoDifferentialexpression and activation of a family of murine peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no15 pp 7355ndash7359 1994

[102] E E Girroir H E Hollingshead P He B Zhu G H Perdewand J M Peters ldquoQuantitative expression patterns of peroxi-some proliferator-activated receptor-120573120575 (PPAR120573120575) protein in

micerdquo Biochemical and Biophysical Research Communicationsvol 371 no 3 pp 456ndash461 2008

[103] P Escher O Braissant S Basu-Modak L Michalik W Wahliand B Desvergne ldquoRat PPARs quantitative analysis in adult rattissues and regulation in fasting and refeedingrdquo Endocrinologyvol 142 no 10 pp 4195ndash4202 2001

[104] D Auboeuf J Rieusset L Fajas et al ldquoTissue distributionand quantification of the expression of mRNAs of peroxi-some proliferator-activated receptors and liver X receptor-120572 inhumans no alteration in adipose tissue of obese and NIDDMpatientsrdquo Diabetes vol 46 no 8 pp 1319ndash1327 1997

[105] N ShawM Elholm andN Noy ldquoRetinoic acid is a high affinityselective ligand for the peroxisome proliferator-activated recep-tor 120573120575rdquo Journal of Biological Chemistry vol 278 no 43 pp41589ndash41592 2003

[106] G Wolf ldquoRetinoic acid as cause of cell proliferation or cellgrowth inhibition depending on activation of one of twodifferent nuclear receptorsrdquoNutrition Reviews vol 66 no 1 pp55ndash59 2008

[107] T T Schug D C Berry N S Shaw S N Travis and N NoyldquoOpposing effects of retinoic acid on cell growth result fromalternate activation of two different nuclear receptorsrdquo Cell vol129 no 4 pp 723ndash733 2007

[108] D C Berry and N Noy ldquoAll-trans-retinoic acid repressesobesity and insulin resistance by activating both peroxisomeproliferation-activated receptor 120573120575 and retinoic acid receptorrdquoMolecular and Cellular Biology vol 29 no 12 pp 3286ndash32962009

[109] D C Berry D DeSantis H Soltanian C M Croniger andN Noy ldquoRetinoic acid upregulates preadipocyte genes to blockadipogenesis and suppress diet-induced obesityrdquo Diabetes vol61 no 5 pp 1112ndash1121 2012

[110] M G Borland C Khozoie P P Albrecht et al ldquoStableover-expression of PPAR120573120575 and PPAR120574 to examine receptorsignaling in human HaCaT keratinocytesrdquo Cellular Signallingvol 23 no 12 pp 2039ndash2050 2011

[111] S E OrsquoSullivan and D A Kendall ldquoCannabinoid activationof peroxisome proliferator-activated receptors potential formodulation of inflammatory diseaserdquo Immunobiology vol 215no 8 pp 611ndash616 2010

[112] Z C Yan D Y Liu L L Zhang et al ldquoExercise reduces adiposetissue via cannabinoid receptor type 1 which is regulated byperoxisome proliferator-activated receptor-120575rdquo Biochemical andBiophysical Research Communications vol 354 no 2 pp 427ndash433 2007

[113] J D McGarry ldquoWhat if Minkowski had been ageusic Analternative angle on diabetesrdquo Science vol 258 no 5083 pp766ndash770 1992

[114] TMoore ldquoVitaminA and carotene the vitaminA reserve of theadult human being in health and diseaserdquo Biochemical Journalvol 31 no 1 pp 155ndash164 1937

[115] GWolfMD Lane and B C Johnson ldquoStudies on the functionof vitamin A in metabolismrdquo Journal of Biological Chemistryvol 225 no 2 pp 995ndash1008 1957

[116] Y Zhang R Li Y Li W Chen S Zhao and G Chen ldquoVitaminA status affects obesity development and hepatic expression ofkey genes for fuel metabolism in Zucker fatty ratsrdquoBiochemistryand Cell Biology vol 90 no 4 pp 548ndash557 2012

[117] M Singh V N Singh and T A Venkitasubramanian ldquoEarlyeffects of feeding excess vitamin A hepatic glycogen bloodlactic acid plasma nefa and glucose tolerance in ratsrdquo LifeSciences vol 7 no 5 pp 239ndash247 1968

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

6 ISRN Hepatology

HepatocyteCell membrane

RE Retinol Retinal RA

Other metabolic pathwaysNuclear

membrane

Cytosol RAOther ligands

RARRXR PPAR120573120575

COUP-TFII UpdownmRNAHNF4120572HNF4120572

RARE

Nucleus

Figure 1 The effects of RA production and other metabolicfactors on the activities of transcription factors associated with aretinoic acid-responsive element (RARE) in the promoter of anRA-targeted gene In primary hepatocytes RA is produced fromretinal derived from retinol Retinol can be esterified into retinylester (RE) or oxidized into retinal The RARE can be occupied byretinoic acid receptor (RAR) retinoid X receptor (RXR) hepatocytenuclear factor 4120572 (HNF4120572) chicken ovalbumin upstreampromoter-transcription factor II (COUP-TFII) and peroxisome proliferator-activated receptor 120573120575 (PPAR120573120575) in the forms of heterodimers orhomodimers These transcription factors receive signals from RAand metabolic pathways and regulate the expression of the RA-responsive gene

is dynamically produced and sent to nucleus where itinteracts with transcription factors associated with RAREin the enhancer regions of the RA-responsive genes Sofar the transcription factors that can be associated with aparticular RARE include RAR RXR COUP-TFII HNF4120572and PPAR120573120575 They form heterodimers or homodimers andbind to RARE to regulate the transcription rate of that geneThe nuclear receptors that occupy the RARE at any givenmoment may be determined by the VA status of the animaland the developmental differentiation and metabolic statesof hepatocytes These transcription factors integrate signalsfrom RA and other metabolic pathways to control the geneexpression positively and negatively Other metabolic signalsin combination with RA may affect the occupancy of thenuclear receptors bound to the RARE and their activationsand may in turn alter the outcomes of the RA-mediatedtranscription responses

2 VArsquos Roles in Glucose Metabolism

As a convenient energy source glucose can be used by all cellsthat are in charge of different physiological functionsGlucoseis metabolized differently in response to hormonal and nutri-tional statuses [113] Hepatocytes utilize and produce glucosedepending on the physiological needs and feeding status ofa subject These processes are regulated by nutritional andhormonal stimuli VA status has been implied to play a role

21 The Effects of VA Status on Hepatic Glycogen ContentsThe roles of VA in glucose metabolism had been suggestedIn 1937 the liver samples of patients who died of diabetesshowed an elevation of VA contents [114] When rats werefed a VA-deficient (VAD) diet to induce VA deficiency theirliver glycogen content was depleted [115] Since VA deficiencyalso caused reduction of food intake in the VAD rats a pair-feeding control group was included The pair-fed rats withequal energy intake as that of VAD rats had higher hepaticglycogen content [115] This depletion of hepatic glycogencontent was attributed to the reduction of glycogenesisfrom trioses rather than directly from glucose [115] Thephenomenon of the depletion of hepatic glycogen contentin the liver of VAD rats has also been observed recently inmy lab [116] On the other hand when rats were fed a dietwith excessive amounts of VA for two days an elevation ofthe hepatic glycogen content in the liver after fasting wasobserved [117] It seems that hepatic VA content is directlycorrelated with the hepatic glycogen content

22 The Effects of Animal VA Statuses and Retinoids onHepatic Gck Expression To initiate the hepatic glucose uti-lization glucose is phosphorylated into glucose 6-phosphateby hexokinases in the first reaction of glycolysis So far fourhexokinase isozymes hexokinase I (A) II (B) III (C) andIV (D) have been identified They have different tissue dis-tributions intracellular locations and kinetic characteristicsMammalian hexokinase IV (D) is also known as glucokinase(GK) (ATP d-hexose 6-phosphotransferase EC 2711) [118ndash121] Mutations of GK have been associated with MODY[122] GK has two unique features that differentiate it fromother hexokinase family members It has low affinity forglucose (higher Km) and it is insensitive to allosteric inhi-bition mediated by physiological concentrations of glucose6-phosphate whereas other hexokinases are sensitive to it[118 121 123 124] In addition to glucose other substrates ofGK include fructose mannose and 2-deoxyglucose [118]

Generally GK activity is mainly observed in the liverand pancreatic islets The 120573-cells and liver GK isoforms havesimilar kinetic properties [125 126] In the short term theGK activity can be regulated via allosteric interactions andcovalent modifications such as binding to GK regulatoryprotein [127] phosphorylation by protein kinase A [128] andinteractionwith a cytosolic GK-associated phosphatase [129]

The long-term regulation of GK activity is done throughthe transcription of its gene Gck which is differentiallyregulated by an upstream promoter in pancreatic 120573-cells anda downstream promoter in hepatocytes [130 131] Using astrain of transgenic mice containing the cDNA of humangrowth hormone gene driven by an upstream Gck promoterfragmentGck expression has been found in certain neuroen-docrine cells of the pancreas pituitary brain gut thyroidand lungs [132] Activation of the upstream or downstreampromoter leads to the generation of a Gck mRNA with aunique 51015840 sequence derived from exon 1120573 or 1L respectivelySince the translation initiation coden is located in the firstexon the GK proteins encoded by the different transcriptsdiffer in the first 15 amino acids at the amino terminus

ISRN Hepatology 7

[130 131] The mechanisms by which the upstream and thedownstream promoters are selectively activated in differentcells have not been revealedThe temporal and special controlof the promoter selectionmust be determined by signals fromdifferentiation and development processes

The upstream and downstream promoters are activatedbased on the hormonal and nutritional conditions of thesubject For example the hepatic but not the pancreatic 120573-cell Gck expression is reduced while fasting and increasedwhile refeeding [130] In the rat liver insulin and glucagonrespectively induce and inhibit the expression of GckmRNA[133ndash135] A long-standing question in the field is the insulin-responsive element (IRE) responsible for the insulin-inducedhepaticGck expression Using the reporter gene constructs tostudy insulin-induced Gck promoter activation has not beensuccessful For example a reporter gene construct containinga fragment of 55 kb hepatic Gck promoter failed to showany response to insulin treatment in rat primary hepatocytes[136] This suggests that the IRE of the hepatic Gck mightbe in an area not included in this 55 kb promoter fragmentAlternatively the unresponsiveness to insulin of the reportergene constructs in the experimental settings could be due tothe short-lived signal from insulin for Gck transcription aswe have shownpreviously [137] Interestingly the hepatocyte-specific enhancer region that controls the activation of liver-specific promoter has been located in the region from minus1003to minus707 relative to the transcription initiation site in primaryrat hepatocytes By contrast this region acts as a silencer inFTO-2B hepatoma cells and has no effects on insulinomacells [138] Further studies are needed to identify the insulin-responsive element in the hepatic Gck promoter

The direct effects of RA on the expression of Gck mRNAin primary rat hepatocytes have been studied Previouslyothers have shown that all-trans RA induced Gck expressionin primary rat hepatocytes However nonadditive effect ofRA on insulin-induced Gck expression was observed [139140] Recently we have shown that retinoids synergized withinsulin to induce Gck expression in primary rat hepatocytes[137] We have observed that all-trans retinol retinal and RAare able to synergize with insulin to induce Gck expressionprobably via the activation of RARRXR in primary rat hepa-tocytes In addition VA status also controls the expression ofhepatic Gck expression [137] The levels of Gck mRNA [116]and its activity [137] in the liver of VAD rats are lower thanthose of VA-sufficient (VAS) controls In addition a singletreatment of RA increases the hepatic Gck expression in rats[137]

23 The Effects of Animal VA Status and Retinoids onPck1 Gene Expression The plasma glucose homeostasis isachieved through its dietary intake and production fromendogenous noncarbohydrate sources During fasting glu-cose is generated via gluconeogenesis The cytosolic form ofphosphoenolpyruvate carboxykinase (PEPCK-C EC41132)which catalyzes the conversion of oxaloacetate into phos-phoenolpyruvate in the presence of GTP [141] has beenconsidered to be the first rate-limiting enzyme of gluconeoge-nesisThe expression of PEPCK-C gene (Pck1) and its activity

have been detected in the liver kidney adipose tissues andsome other tissues [141ndash143] Other than gluconeogenesisPEPCK-C activity has been considered to be responsible forglyceroneogenesis and cataplerosis [144] Since no allostericregulator of PEPCK-C has been identified its activity isprimarily controlled by the level of Pck1mRNA [141ndash143]

The transcription of hepatic Pck1 is regulated by hor-monal and nutritional stimuli In the liver fasting diabetescarbohydrate-free diets and high-fat diets increase Pck1 geneexpression whereas refeeding insulin treatment and high-carbohydrate diets decrease Pck1 gene expression Glucagonglucocorticoids thyroid hormone and RA induce hepaticPck1 expression while insulin and glucose inhibit it [145]

The transcription regulation of Pck1 has been studiedextensively [142 143] The protein-binding sites at the prox-imal region of rat Pck1 promoter have been determined byDNase I footprinting assays [146 147] Multiple regulatoryelements including distal proximal cyclic AMP-responsiveelement (CRE) [148] have been identified Proteins in ratliver nuclear extracts can interact with the two CREs andsix additional binding sites (P1 to 6) [142] The transcrip-tion factors that bind to these sites include HNF4120572 [149]glucocorticoid receptor [148 150ndash153] RAR [154ndash157] TR[154 158] LXR [159] COUP-TF [149] the Forkhead familyof transcription factors [160] CEBP and cAMP regulatoryelement-binding (CREB) protein [161] and SREBP-1c [162163] Additionally transcription coactivators such as CREB-binding protein (CBP) [164] steroid receptor coactivator 1(SRC1) [165] and peroxisome proliferator-activated receptorgamma coactivator-1-alpha (PGC-1120572) [166] also participatein the regulation of hepatic Pck1 gene expression

Using reporter gene assays and hepatoma cells twoRAREs have been identified in the hepatic Pck1 promoter[154 155 167]WhenPEPCKbovine growth hormone (bGH)transgenic mouse strains are used VA deficiency causes thereduction of the transgenersquos transcription [167]The RARE1 isconsidered to be important for mediating the RA-regulatedPck1 expression in the mouse liver [157] In mice VA statusaffects the association of RNApolymerase II and histone codeof Pck1 promoter [168 169] Later on these RAREs have beenshown to bind toHNF4120572 RXR120572 RAR120572 PPAR120572 and COUP-TFII [170]

In an attempt to study the lipophilic molecules that affectinsulin-regulated gene expression in primary rat hepatocyteswe have obtained lipophilic extract (LE) from the rat liverMyoriginal study has shown that this LE induces Pck1 expressionand attenuates insulin-mediated suppression of Pck1 tran-scription in primary rat hepatocytes [171] Interestingly thesame LE synergizes with insulin to induce Gck expression inthe same cells [137]The activemolecules in the LE are retinoland retinal [137] We have shown that retinol retinal andRA all can affect insulin-suppressed Pck1 expression [172]In rat primary hepatocytes the proximal one of the twoRAREs in the rat Pck1 promoter [154ndash156] is responsiblefor mediating the retinoid effects [172] The expression ofhepatic Pck1mRNA in rats seems to respond to VA deficiencydifferently from that in mice We have shown that the hepaticPck1mRNA level in the Zucker lean (ZL) rats is not reduced

8 ISRN Hepatology

Hepatocyte

Induction

Induction

Induction

1 2

Gck

Pck1

Cell membraneCytosol

RA RA

RARESynergy

Signalcascade Insulin

AttenuationNuclear

membrane NucleusRAREs

Inhibitio

n

Figure 2 RA synergizes with insulin to induce Gck expressionand attenuates insulin-suppressed Pck1 expression RA inducesthe expression levels of Gck and Pck1 via the activation of bothRARRXR (the oval dimmers on the RAREs) in the absenceof insulin Insulin alone stimulates the expression of Gck andsuppresses the expression of Pck1 In the presence of both insulinand RA the expression of Gck is further increased (synergy) Onthe other hand the insulin-mediated suppression of Pck1 expressionis attenuated This is because RA still induces Pck1 expressionvia activation of RAR in the presence of insulin Therefore Pck1transcript level in the RA + insulin group is higher than that in theinsulin group (attenuation)

in VA-deficient state [116] VA deficiency only reduces thehepatic Pck1mRNA in the Zucker fatty (ZF) rats [116]

It is important to note that the respective activities of GKand PEPCK-C are induced in different physiological condi-tions For example insulin induces Gck and suppresses Pck1expression as shown in Figure 2 In primary rat hepatocytesactivation of either RARs or RXRs by RA is sufficient toinduce the expression of both Pck1 [172] and Gck [137] How-ever activation of RAR potentiates (for the insulin-mediatedinduction of Gck expression) and attenuates (for the insulin-mediated suppression of Pck1 expression) insulin actionsat the same time in the same hepatocytes For Gck RA-mediated activation of RARs and RXRs can be potentiated byinsulin [137] which results in the synergy For Pck1 only RA-activated RXRs but not RARs are inhibited by insulin whichresults in the attenuation [172] This causes the production ofmore Pck1 mRNA in the presence of RA than in the absenceof it even in the insulin-suppressed state It indicates that themechanisms of RA-mediated activation of RARs and RXRsprobably depend on the promoter context or the isoformsassociated with the promoters of their downstream genesin the presence of insulin Therefore the roles of retinoidsin hepatic glucose metabolism deserve further investigationespecially the roles of the interactions between retinoidsand insulin signaling pathways in the regulation of genetranscription

24 Role of RBP4 in Insulin Resistance Plasma VA is boundto RBP4 which is mainly produced in the liver [13] TheRbp4 mRNA is also expressed to a certain extent in adipose

tissues and kidney [13] In the plasma retinol-RBP4 complexis associated with transthyretin (TTR) a process to increasethe size of the holo-RBP4-TTR complex to reduce the lossduring renal filtration [173]

Recently the plasma RBP4 has been suggested to playroles in metabolic homeostasis It has been reported thatinsulin-resistant human subjects and animals have higherplasma RBP4 levels than normal ones due to its elevatedproduction from adipose tissues [174] In mice RBP4administration has been shown to reduce insulin sensitivityand increase the expression levels of hepatic gluconeogenicgenes such as Pck1 and the catalytic subunit of glucose 6-phosphatase (G6pc) [175] Additionally reduction of plasmaretinol and RBP levels has been reported in type 1 diabeticpatients [176] and in streptozotocin- (STZ-) induced diabeticrats [177] Rbp4 knockout mice have improved insulin sen-sitivity [175] The treatment fenretinide a synthetic retinoidderivative that disrupts the association of RBP4 and TTRimproves insulin sensitivity in HFD-induced obese mice[175]

When a compound specifically developed to disrupt theRBP4 and TTR interaction was used to treat mice it suc-cessfully disrupted the formation of RBP4-TTR complex andcaused the reduction of plasma RBP4 level [178] Howeverthe reduction of plasma RBP4 level did not result in animprovement of insulin sensitivity [178] In addition theimprovement of insulin sensitivity in Rbp4 knockout micecould not be observed in this study [178] Therefore the ele-vation of insulin sensitivity in mice treated with fenretinideis probably due to a mechanism other than the disruption ofRBP-TTR complex and reduction of plasma RBP4 levels

3 Roles of VA in FA and TG Metabolism

FAs are needed for many aspects of cellular functions fromsignal transduction to energy production The continuoussurvival of a given cell depends on the constant energysupplies from the environment or storage sources Thestorage of FA in the form of TG ensures the constant energysupply in a cell or organism for a prolonged period oftime when environment energy is limited In animals thehomeostasis of FA and TG is dynamically regulated by theliver and the adipose tissues in response to nutritional andhormonal stimuli [179 180] During fasting or starvation FAsare released from adipose depots after lipolysis and oxidizedin the liver and muscle for energy production [181] Afterrefeeding dietary and newly synthesized FAs are convertedto TGs for the storage in the adipose tissues [182] On theother hand the altered regulation of this system may causeproblems For example the excessive synthesis and storage ofFAs in the form of TGs can cause the development of obesityand other metabolic diseases

31 The Effects of VA Status on the Body Fat and Plasma LipidProfile VA was first recognized as a dietary lipophilic factorwhich was essential to support the normal growth of labanimals [3 4] Subsequently it was observed that along withthe reduction of body mass the VAD rats that had been fed

ISRN Hepatology 9

aVADdiet at weaning (21 days old) formore than 9weeks hadreduction of carcass fat but not cholesterol content [183] Onthe other hand this reduction of body fat was not observedin the rats of the pair-feeding group which were given thesame amount of a VAS diet in weight and calories as theone consumed by the VAD rats [183] These results indicatethat the reduction of food intake alone could not be used toexplain the depletion of body fat in the VAD rats

The VA status also seems to affect the hepatic expressionof apo AI mRNA The expression of hepatic apo AI hasbeen shown to be sensitive to VA status [184] When theLewis strain rats develop VA deficiency the expression levelof hepatic but not intestinal apo AI mRNA is elevated Thisinduction is dropped upon single dosage of RA treatment[184] On the other hand in the intestine and liver of VA-deficient Wistar rats both all-trans RA and 9-cis RA caninduce apo AI mRNA levels [185] The same treatment canonly induce the mRNA level of apo CIII in the intestine butnot in the liver [185] In humans the plasma VA levels arepositively correlated with the elevations of proteins of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiapatients [186]

When male Wistar rats were fed a VAD diet for 3 monthsafter weaning (21 days old) they had lower plasma TGs andcholesterol levels than the control ones fed a VAS diet [187]When the hepatic synthesis of FAs and phospholipids wasanalyzed in the liver slices the incorporations of [14C]cholineinto phosphatidylcholine and [14C]acetate into FAs were alsoreduced in the VAD rats compared with their VAS controls[187] The VAD rats had lower activities and mRNA levels ofacetyl-CoA carboxylase but higher activity and mRNA levelof carnitine palmitoyltransferase-I than VAS rats had [187]These results demonstrate that there is a reduction of hepaticfatty acid synthesis along with an induction of hepatic fattyacid oxidation in the liver of VAD rats

My lab has conducted experiments and shown that VAstatus affects the obesity development in ZF rats and controlsplasma TG levels in ZL and ZF rats [116] ZF rats a ratmodel of obesity development [188] develop obesity dueto a missense mutation in the extracellular domain of allleptin receptor isoforms [189ndash191] They have been used forthe studies of obesity insulin resistance and other aspectsof metabolic diseases [192 193] We have analyzed growthplasma parameters and expression levels of hepatic genes ofmale ZL and ZF rats fed a VAD or a VAS diet at weaning(21 days of age) for 8 weeks Body masses of ZL and ZF ratsfed the VAD diet are lower than those of their correspondingcontrols fed the VAS diet at the end of the feeding periodThe VAD ZL or ZF rats begin to take less food than the VASones after five weeks on the diet The VAD ZL or ZF rats havelower plasma glucose TG insulin and leptin levels than theircorresponding VAS rats have The liver glycogen content netweights of epididymal fat and liver and fat-to-body massratio (ZL only) in the VAD rats are also lower than those inthe VAS ones [116] This demonstrates that VA status affectsplasma TG levels in both ZF and ZL rats and the obesitydevelopment in ZF rats This phenomenon may be caused by

the combination of VA deficiency and hypoinsulinemia sinceinsulin secretion is impaired in the VAD rats [194]

32 The Development of Hypertriglyceridemia inPatients Receiving Retinoic Acid-Based Treatments

321 The Uses of RA-Based Medicines in Clinic RA-basedmedicines tretinoin (all-trans RA) isotretinoin (13-cis RA)and alitretinoin (9-cis RA) have been used in clinic to treatdiseases such as acute promyelocytic leukemia and skindisorders [11] In fact isotretinoin has been widely used totreat severe acne Early clinical observations indicate that themedical use of isotretinoin in human subjects results in theelevation of their plasma TG levels [195ndash197] A significantportion of patients with acne receiving isotretinoin treatmentdeveloped hypertriglyceridemia [9 10] In addition thesystemic administration of isotretinoin in patients with acneresulted in the elevation of plasma levels of alanine amino-transferase (ALT) and aspartate aminotransferase (AST)indicating the liver damage [198]The hypertriglyceridemia isalso associated with reduced insulin sensitivity and elevatedTG in the very-low-density lipoprotein (VLDL) fraction[195] The treatment of all-trans RA resulted in body massgain and hypertriglyceridemia in patients with acute promye-locytic leukemia [199 200] Moreover RA treatment alsoraises plasma TG levels in rats [201ndash203]

322 The Mechanism of RA-Mediated Hypertriglyceridemiain Patients Apo CIII is produced from liver and consideredan inhibitor of LPL activity [204] Mice with Apoc3 geneknockout have hypotriglyceridemia and enhanced in vivoVLDL-TG clearance [205] On the other hand transgenicmice with overexpression of apo CIII develop hypertriglyc-eridemia [206] The RA-induced hypertriglyceridemia hasbeen attributed to RA-induced apo CIII expression

In healthy human subjects isotretinoin treatment causesa rise of plasma apo CIII protein level [207]This is caused bythe induction of Apoc3 mRNA via the activation of RXR ata RARE in its promoter [207] The plasma TG levels in ratstreated with RXR-specific agonist (LG100268) are inducedrapidly and constantly [208] This results in the reducedactivity of LPL in the heart and skeletal muscle of thoseanimals [208] The RARE is identified in the C3P regionwhich controls the hepatic specific expression of Apoc3 gene[75] Interestingly the same site is also considered to beresponsible for mediating the effects of HNF4120572 and COUP-TFII onApoc3 gene expression [209]The expression ofApoc3seems to be regulated differently by the C3P-binding proteins[75]

It is worth to note that insulin suppresses Apoc3 mRNAexpression in STZ-induced diabetic mice [210] In additionthe activation of RXR by LG100268 treatment induces insulinsensitivity and reduces TG levels in obese and diabetic mice[211] The understanding of the regulatory mechanism thatintegrates hormonal and nutritional signals at the regulatorysites such as C3P in Apoc3 promoter will shed some lightson the regulation of hepatic lipid homeostasis It will also

10 ISRN Hepatology

provide a novel target for the treatment of the RA-inducedhypertriglyeridemia

323 The Effects of RA Treatment on Obesity Developmentin Mice Interestingly the RA administration in rodentscauses reduction of body mass as summarized in [212] Thiskind of reduction of body mass has been associated withenhancement of insulin sensitivity in genetic [213] or DIOmice [108] The mechanisms of RA-mediated attenuation ofinsulin resistance have been thought to be the induction ofenergy expenditure through PPAR120573120575 activation [108] andthe inhibition of adipogenesis throughRXR120574 activation [109]On the other hand retinol can be metabolized in adipose tis-sues [214]Themice with deletion ofRaldh1 gene (Raldh1minusminus)have elevated retinal in their adipose tissues and are resistantto diet-induced obesity and insulin resistance [26] This hasbeen attributed to the suppression of adipogenesis by retinal-inhibited activation of PPAR120574 and RXR [26] It is interestingto note that either retinal or RA can inhibit the adipogenesisand cause the improvement of insulin sensitivity in micebased on these studies

33 Roles of VA and Retinoids in the Regulation of HepaticLipogenic Gene Expression Insulin resistance diabetes andother metabolic abnormalities are associated with profoundchanges of hepatic lipid and glucose metabolismThis can beattributed at least in part to the altered expression of genesinvolved in glucose and lipid metabolism [215] The hepaticlipogenesis contributes to the homeostasis of FAs and TGs

331 The Regulation of Hepatic Srebp-1c Expression by VAStatus and Retinoids Treatment Insulin plays an essentialrole in the hepatic FA synthesis It has been known for a whilethat insulin is needed for the glucose usage for lipogenesis andCO2production in the liver [216] The hepatic FA synthesis

rises sharply and continuously after rats are fasted and thenrefed a high-carbohydrate diet [217] The amount of fattyacid synthase (FAS) is induced in normal rats refed a high-carbohydrate diet after fasting and in STZ-induced diabeticrats after insulin administration [218] In the insulin-deficientrats the induction of FAS after refeeding occurs only wheninsulin injection is injected [219] a process attributed to theinduction of FAS gene (Fas) [220 221]

The transcription of hepatic Fas is controlled by a tran-scription factor named SREBP-1c [222] In the liver-specificSrebp-1c knockoutmouse liver the induction of Fas and otherlipogenic genes by refeeding after fasting is blunted [223]Interestingly insulin also specifically induces the Srebp-1cexpression in the liver [224] via two liver X receptor elements(LXREs) and one sterol-responsive element (SRE) [225]However in liver-specific insulin receptor knockoutmice theinduction of hepatic Srebp-1c by refeeding largely remainedunchanged [226] This suggests that nutrient-derived signalsmay activate downstream of insulin receptor signaling path-way to regulate Srebp-1c expression and hepatic lipogenesis[226]

As stated in the previous section my research group hasobserved that the VAD ZL and ZF rats have lower plasma TG

levels than their VAS controls [116] This is accompanied bythe reduction of the hepatic expression of Srebp-1cmRNA inVA-deficient animals [116] My research group has reportedfor the first time that retinoids synergize with insulin toinduce the expression of Srebp-1c in primary rat hepatocytes[227] Further analysis of the Srebp-1c promoter reveals thatthe previous identified LXREs responsible for mediatinginsulin-induced Srebp-1c expression are also RAREs [227]These observations show that retinoids (nutritional) andinsulin (hormonal) signals converge to regulate the FAsynthesis in the liver

332 The Effects of VA Catabolism on the Regulation of Srebp-1c Expression in Primary Rat Hepatocytes More recentlyretinoids have been proposed to play roles in glucose and lipidmetabolism and to maintain energy homeostasis [228 229]VA (retinol) is reversibly converted into retinal and retinalis irreversibly converted into RA [23] Retinal the precursorof RA production is able to synergize with insulin to inducethe Srebp-1c expression in primary rat hepatocytes [227]This suggests that the dynamic production of RA influencesthe expression of hepatic lipogenic genes It has led us toinvestigate the roles of RA production in the insulin-resistantanimals

In the liver of the Raldh1minusminus mice RA production isreduced in response to a load of retinol [230] The Raldh1minusminusmice are resistant to the development of obesity and insulinresistance after being fed an HFD [26] This is attributed tothe elevation of retinal content due to the lack of conversionof retinal to RA in the adipose tissues of the Raldh1minusminusmice Additionally the liver of the Raldh1minusminus mice hasaltered regulation of the genes for gluconeogenesis andsignificantly attenuated hepatic TG synthesis indicating theimportant role of hepatic VAmetabolism in glucose and lipidhomeostasis [231]

The hepatic expression levels of RALDH1 and RALDH2are induced in mice fed a high-cholesterol diet [232] SREsare located in the promoters of these two genes whichare induced by SREBP-1c overexpression The expression ofSrebp-1c is induced by the oxysterols derived from the high-cholesterol diet [232] This research work demonstrates theinteraction of cholesterol and RA metabolism in the liver Inaddition it has been shown that the level of Raldh1mRNA iselevated in the kidney of dbdb mice [233] Both dbdb miceand ZF rats develop obesity due to the mutation of leptinreceptor [234]

In an attempt to understand the roles of VA metabolismin the states of metabolic diseases we have compared theexpression levels of enzymes responsible for the productionof retinal and RA in the freshly isolated and cultured primaryhepatocytes from ZL rats and ZF rats [45] We have foundthat in the primary rat hepatocytes the enzymes responsiblefor the conversions of retinol to retinal and from retinal toRA are most likely RDH2 and RALDH1 respectively Theexpression levels of Raldh1 mRNA and its protein are higherin hepatocytes from ZF rats than in those from ZL rats[45] When overexpressed RALDH1 introduces the retinal-mediated induction of Srebp-1c in INS-1 cells which do not

ISRN Hepatology 11

respond to retinal in our previous study [227] These resultsindicate that insulin-resistant animals such as ZF rats mayhave alterations in retinoids metabolism

Thus we have hypothesized that the change of RAproduction from the oversupply of dietary VA due to thehyperphagia of ZF rats results in higher Srebp-1c expressionin ZF hepatocytes [45] The elevated SREBP-1c expressioncan further induceRaldh1 expression to create a feed-forwardmechanism that could be one of the reasons responsible forthe increased lipogenesis in the liver of ZF rats All of theseobservations indicate the potential roles of RA metabolismin the development of obesity and insulin resistance whichdeserves to be further studied

4 VArsquos Roles in Mediating Hepatic InsulinAction and Insulin Resistance

41 Insulin and Its Signal Transduction The insulin moleculeis made of two chains linked by one intra- and one interchaindisulfide bonds [235] The insulin receptor is a transmem-brane and heterotetramer tyrosine kinase receptor (two 120572and two 120573 subunits) linked by disulfide bonds as well [236]The binding of insulin to its receptor causes conformationchanges and transphosphorylation of the 120573-subunit tyrosinekinase [237 238] which initiates the signal transduction[239] Protein-protein interactions are involved in the trans-duction of insulin signalThe signal is transduced bymultiplecomponents in a complex network containing cascades ofkinases and phosphatases [240 241] The first intracellularcomponents mediating insulin signals are insulin recep-tor substrates (IRSs) protein molecules phosphorylated byinsulin receptor 120573-subunit and mediating insulin signals[242]

The insulin signal event is further amplified byphosphatidylinositide 3-kinases (PI3K)protein kinaseB (PKBAkt) pathway and GRB2mitogen-activated proteinkinase (MAPK) pathway [243ndash245] Another serinethre-onine kinase that can be activated by PI3K is the atypicalprotein kinase C [246] Human liver expresses severalprotein-tyrosine phosphatases (PTPs) [247] Okadai acid aninhibitor of protein phosphatase type 2A and type 1 inhibitsglycogen synthesis and insulin-stimulated Gck expression inprimary rat hepatocytes indicating that dephosphorylationmechanism may also participate in mediating insulinsignaling [248] These components are shared by insulin-likegrowth factor (IGF) receptor and involved in mediatinginsulin and IGF signals [249]

42 Metabolic Diseases and Insulin Resistance The rise ofthe number of people with one or more metabolic diseasessuch as obesity and diabetes in the world has become apublic health problem [250] The interactions of genetic andenvironmentalnutritional factors may be responsible for thecurrent rise of metabolic diseases The long evolutionaryprocess has equipped human and animal bodieswith a varietyof regulatory mechanisms controlling these interactions [251252] Human diets contain not only energy derived frommacronutrients but also micronutrients and other factors

which may influence the metabolic outcomes The roles ofindividual micronutrients in the development of metabolicdiseases are still unrevealed

One common property of human obesity and NIDDMis insulin resistance in which a given amount of insulinproduces less than normal physiological responses Dietaryfactors and manipulations have been considered to play arole in the development of insulin resistance in humans andanimals For example feeding an HFD to young and insulin-sensitive subjects for two days causes the development ofglucose intolerance [253] In the skeletal muscle of rats fedan HFD for 8 weeks the insulin-induced glucose uptakeis impaired [254] FFAs have been considered the factorsresponsible for HFD-induced leptin and insulin resistance[255ndash257]

43 Hepatic Insulin Resistance and Vicious Cycle The liverplays an essential role in the control of glucose andlipid homeostasis It coordinately regulates the processesin responses to nutritional and hormonal stimuli Insulinplays a major role in directing the liverrsquos metabolic status[258] which is partially attributed to the regulation of theexpression of genes involved in hepatic glucose and lipidmetabolism [215 259]

Insulin controls the expression of a variety of genesinvolved in glycolysis glycogenesis and lipogenesis andgluconeogenesis in the liver [145] Generally hepatic lipidand glucose metabolism is altered with the development ofinsulin resistance in obesity and NIDDM [258] This canbe reflected in the expression of insulin-regulated hepaticgenes for glucose and FA metabolism When the liver isinsulin sensitive insulin stimulates lipogenesis and inhibitsgluconeogenesis For example to regulate hepatic glucosehomeostasis insulin increases the expression of Gck gene[119 120] and Srebp-1c [224] a family member of SREBPswhich regulate the hepatic cholesterol and FA biosynthesisand their homeostasis [260] It suppresses the expressionof Pck1 [142] and G6pc [145] which control the first andlast steps of gluconeogenesis respectively When the liver isinsulin resistant insulin no longer inhibits gluconeogenesisHowever the liver still keeps the elevated lipogenesis Theelevated FA biosynthesis in the insulin-resistant state furtherfacilitates insulin secretion from pancreatic 120573-cells whichprobably enhances lipogenesis and results in a vicious cycle[113 261] The coexistence of the hepatic insulin resistanceand sensitivity at the gene expression level has been observedin rodent obese and diabetic models [215 258] Howeverthe mechanism of this coexistence of insulin sensitivity andresistance has not been revealed [261]

Recently the SREBP cleavage-activating protein gene(Scap) an escort protein necessary for generating nuclearforms of SREBPs has been knocked out in insulin-resistantobob mice [262] Deficiency of hepatic Scap reverses liverlipogenesis and steatosis in obobmice However the plasmalevels of glucose and insulin and the hepatic expression levelsof Pck1 andG6pcwere not different between the control obobmice and the obob mice with liver-specific Scap knockout[262] It seems that the suppression of hepatic FA synthesis

12 ISRN Hepatology

is not sufficient to correct insulin resistance Whether otherfactors play a role in the hepatic insulin resistance is still anopen question

The clinical use of RA-based medicine such asisotretinoin (13-cis RA) caused elevation of plasma TGlevels in human subjects [195ndash197] This increase in plasmaTG levels is also observed in rats [201ndash203] From our VAstatus studies we have shown that VA status affected theobesity development in ZF rats and reduced plasma insulinand TG levels in ZL and ZF rats suggesting improvement ofinsulin sensitivity [116] The hepatic expression of Srebp-1cwas reduced in VA-deficient animals [116] RA synergizeswith insulin to induce the expression of Srebp-1c in primaryrat hepatocytes [227] On the other hand RA treatmentinduces Pck1 expression and attenuates insulin-mediatedsuppression of its expression in primary rat hepatocytes [172]All of these observations demonstrate that RA attenuatesinsulin action (insulin-suppressed Pck1 expression) andstill promotes insulin action (insulin-induced Srebp-1cexpression) in the same primary hepatocytes

44 Possible Mechanism by Which RA Production Causes theDevelopment of the Vicious Cycle in Hepatocytes Could RAor other metabolites from VA catabolism be a factor thatcontributes to the hepatic insulin resistance and the viciouscycleUsing the regulation ofPck1 and Srebp-1c as themodel Ihave come upwith the following scheme to show that retinoidmetabolism could be a factor that causes the vicious cycle inthe liver As shown in Figure 3(a) in insulin-sensitive hepa-tocytes RA derived from retinal coordinates with insulin toregulate the expression of Srebp-1c and Pck1 The SREBP-1cprotein is processed to mature form a step that can be facili-tated by insulin [263] The mature form of SREBP-1c entersinto the nucleus and induces the mRNA levels of Raldh1and Fas which are respectively transcribed into RALDH1and FAS RALDH1 catalyzes the conversion of retinal to RAFAS catalyzes the synthesis of palmitate which is esterifiedinto TGs or elongated to longer FAs The Pck1 mRNA isused to translate into PEPCK-C protein which contributesto glucogenogenesis In the insulin-resistant hepatocytes asshown in Figure 3(b) the elevation of Raldh1 expressiondue to leptin deficiency [45] or induction of SREBP-1c byhigh-cholesterol feeding [232] induces the production of RAThe elevated RA levels will stimulate the transcription ofSrebp-1c and Pck1 This leads to more production of SREBP-1c and its mature form in the presence of higher insulinlevels in the insulin-resistant state The induction of SREBP-1c further enhances the transcription of Raldh1 and Fas andtheir corresponding proteins for the production of moreRAs and FAs respectively The RA production and SREBP-1c expression form a feed-forward cycle which causes moreTG and RA production in the insulin-resistant liver At thesame time more of the PEPCK-C protein is generated dueto the elevated Pck1 transcription by RA stimulation whichis not responsive to insulin inhibition as we have shown in[172] This leads to elevated gluconeogenesis in the insulin-resistant liver Eventually the phenotypes appear as if insulin

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1cRetinal

RALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(a) Insulin-sensitive hepatocytes

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1c

RetinalRALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(b) Insulin-resistant hepatocytes

Figure 3 The effects of RA on the insulin-regulated Srebp-1cand Pck1 expression levels the protein levels of SREBP-1c theexpression levels of Raldh1 and Fas and the fatty acid synthesisand gluconeogenesis in insulin-sensitive (a) and insulin-resistant (b)hepatocytes Please see the text in this paper for description Uparrows next to the text indicate induction The intensified weight ofthe lines indicates the induction of that part of the pathway

no longer suppresses gluconeogenesis while it still stimulatesFA synthesis in the insulin-resistant state

5 Perspectives and Future Directions

I have proposed a mechanism by which VA metabolismcontributes to the development of hepatic insulin resistanceIt explains some observations reported in the previous studiesof rodent obese and diabetic models [215 258] However itleavesmore open questionsThefirst one iswhat the initiationfactor is So far the elevated expression of Raldh1 mRNA inthe liver has been observed in ZF rats [45] and mice fed ahigh-cholesterol diet [232] These two conditions cause a lotof physiological changes such as overfeeding in ZF rats andchange of cholesterol biosynthesis in response to the feedingof high-cholesterol diet Knocking down Raldh1 specificallyin hepatocytes is needed to answer these questions The

ISRN Hepatology 13

second question is whether RA synthesis in hepatocytesis a regulated process in response to dietary or hormonalstimulations If Raldh1 is a downstream gene of SREBP-1cit should be regulated when the SREBP-1c level changes Asthe expression of Srebp-1c responds to insulin stimulation andoxysterols the regulation of Raldh1 expression in the livershould be studied The third question is why it is RALDH1but not other RALDHs Specific inhibitors of RALDHsmay be needed to answer this question Last question iswhether we can attenuate insulin resistance by suppressingthe RALDH1 activity in the liver It has been shown thatRaldh1minusminus mice are still insulin sensitive when they are onan HFD [26] This has been attributed to the effects on theadipogenesis However the liver of those knockout mice hasreduced lipid synthesis [231] Further studies are warrantedto answer all of these questions Hopefully it can become anintervention point for the treatment of insulin resistance andmetabolic diseases

Acknowledgments

This work was financially supported by a research grantfrom Allen Foundation Inc (to Guoxun Chen) a start-up fund from the University of Tennessee at Knoxville (toGuoxun Chen) and a Scientist Development Grant fromthe AmericanHeart Association (09SDG2140003 to GuoxunChen) The author thanks his colleague Dr Lauren Gellar forreading through this paper and offering her edits

References

[1] F G Hopkins ldquoFeeding experiments illustrating the impor-tance of accessory factors in normal dietariesrdquo The Journal ofPhysiology vol 44 no 5-6 pp 425ndash460 1912

[2] K J Carpenter ldquoA short history of nutritional science part 3(1912ndash1944)rdquo Journal of Nutrition vol 133 no 10 pp 3023ndash30322003

[3] E V McCollum and M Davis ldquoThe necessity of certain lipinsin the diet during growthrdquo Journal of Biological Chemistry vol15 no 1 pp 167ndash175 1913

[4] T B Osborne and L B Mendel ldquoFeeding experiments with fat-free food mixturesrdquo Journal of Biological Chemistry vol 12 no1 pp 81ndash89 1912

[5] R D Semba ldquoOn the lsquoDiscoveryrsquo of Vitamin Ardquo Annals ofNutrition and Metabolism vol 61 no 3 pp 192ndash198 2012

[6] R Blomhoff and H K Blomhoff ldquoOverview of retinoidmetabolism and functionrdquo Journal of Neurobiology vol 66 no7 pp 606ndash630 2006

[7] A Sommer ldquoVitamin A deficiency and clinical disease anhistorical overviewrdquo Journal of Nutrition vol 138 no 10 pp1835ndash1839 2008

[8] K J Rothman L L Moore M R Singer U-S Nguyen SMannino and A Milunsky ldquoTeratogenicity of high vitamin Aintakerdquo The New England Journal of Medicine vol 333 no 21pp 1369ndash1373 1995

[9] S Bershad A Rubinstein and J R Paterniti Jr ldquoChanges inplasma lipids and lipoproteins during isotretinoin therapy foracnerdquoThe New England Journal of Medicine vol 313 no 16 pp981ndash985 1985

[10] N Rodondi R Darioli A-A Ramelet et al ldquoHigh risk forhyperlipidemia and the metabolic syndrome after an episodeof hypertriglyceridemia during 13-cis retinoic acid therapy foracne a pharmacogenetic studyrdquo Annals of Internal Medicinevol 136 no 8 pp 582ndash589 2002

[11] H-U Klor A Weizel M Augustin et al ldquoThe impact oforal vitamin A derivatives on lipid metabolism what recom-mendations can be derived for dealing with this issue in thedaily dermatological practicerdquo Journal of the German Societyof Dermatology vol 9 no 8 pp 600ndash607 2011

[12] R M Russell ldquoThe vitamin A spectrum from deficiency totoxicityrdquoThe American Journal of Clinical Nutrition vol 71 no4 pp 878ndash884 2000

[13] A C Ross B Caballero R J Cousins K L Tucker and T RZiegler Modern Nutrition in Health and Diseases 11th edition2012

[14] E H Harrison ldquoMechanisms of digestion and absorption ofdietary vitamin Ardquo Annual Review of Nutrition vol 25 no 1pp 87ndash103 2005

[15] M R Lakshman ldquoAlpha and omega of carotenoid cleavagerdquoJournal of Nutrition vol 134 no 1 pp 241ndash245 2004

[16] I Potrykus ldquoNutritionally enhanced rice to combat malnutri-tion disorders of the poorrdquo Nutrition Reviews vol 61 no 6 ppS101ndashS104 2003

[17] A Wyss ldquoCarotene oxygenases a new family of double bondcleavage enzymesrdquo Journal of Nutrition vol 134 no 1 pp 246ndash250 2004

[18] R Kawaguchi J Yu J Honda et al ldquoA membrane receptor forretinol binding protein mediates cellular uptake of vitamin ArdquoScience vol 315 no 5813 pp 820ndash825 2007

[19] P Alapatt F Guo S M Komanetsky et al ldquoLiver retinoltransporter and receptor for serum retinol-binding protein(RBP4)rdquo Journal of Biological Chemistry vol 288 no 2 pp1250ndash1265 2013

[20] A R Moise N Noy K Palczewski and W S Blaner ldquoDeliveryof retinoid-based therapies to target tissuesrdquo Biochemistry vol46 no 15 pp 4449ndash4458 2007

[21] G Duester ldquoFamilies of retinoid dehydrogenases regulatingvitamin A function Production of visual pigment and retinoicacidrdquo European Journal of Biochemistry vol 267 no 14 pp4315ndash4324 2000

[22] M Theodosiou V Laudet and M Schubert ldquoFrom carrotto clinic an overview of the retinoic acid signaling pathwayrdquoCellular andMolecular Life Sciences vol 67 no 9 pp 1423ndash14452010

[23] J L Napoli ldquoInteractions of retinoid binding proteins andenzymes in retinoidmetabolismrdquoBiochimica et BiophysicaActavol 1440 no 2-3 pp 139ndash162 1999

[24] X Chai M H E M Boerman Y Zhai and J L NapolildquoCloning of a cDNA for liver microsomal retinol dehydro-genase A tissue-specific short-chain alcohol dehydrogenaserdquoJournal of Biological Chemistry vol 270 no 8 pp 3900ndash39041995

[25] B X Wu G Moiseyev Y Chen B Rohrer R K Crouch andJ-XMa ldquoIdentification of RDH10 an all-trans retinol dehydro-genase in retinal Muller cellsrdquo Investigative Ophthalmology andVisual Science vol 45 no 11 pp 3857ndash3862 2004

[26] O Ziouzenkova G Orasanu M Sharlach et al ldquoRetinalde-hyde represses adipogenesis and diet-induced obesityrdquo NatureMedicine vol 13 no 6 pp 695ndash702 2007

14 ISRN Hepatology

[27] J L Napoli ldquoPhysiological insights into all-trans-retinoic acidbiosynthesisrdquo Biochimica et Biophysica Acta vol 1821 no 1 pp152ndash167 2012

[28] G Wolf ldquoTissue-specific increases in endogenous all-transretinoic acid possible contributing factor in ethanol toxicityrdquoNutrition Reviews vol 68 no 11 pp 689ndash692 2010

[29] P V Bhat J Labrecque JM Boutin A Lacroix andA YoshidaldquoCloning of a cDNA encoding rat aldehyde dehydrogenase withhigh activity for retinal oxidationrdquoGene vol 166 no 2 pp 303ndash306 1995

[30] M Lin M Zhang M Abraham S M Smith and J LNapoli ldquoMouse retinal dehydrogenase 4 (RALDH4) molecularcloning cellular expression and activity in 9-cis-retinoic acidbiosynthesis in intact cellsrdquo Journal of Biological Chemistry vol278 no 11 pp 9856ndash9861 2003

[31] F A Mic A Molotkov X Fan A E Cuenca and GDuester ldquoRALDH3 a retinaldehyde dehydrogenase that gener-ates retinoic acid is expressed in the ventral retina otic vesicleand olfactory pit during mouse developmentrdquo Mechanisms ofDevelopment vol 97 no 1-2 pp 227ndash230 2000

[32] X Wang P Penzes and J L Napoli ldquoCloning of a cDNAencoding an aldehyde dehydrogenase and its expression inEscherichia coli recognition of retinal as substraterdquo Journal ofBiological Chemistry vol 271 no 27 pp 16288ndash16293 1996

[33] A Molotkov and G Duester ldquoGenetic evidence that retinalde-hyde dehydrogenase Raldh1 (Aldh1a1) functions downstreamof alcohol dehydrogenase Adh1 in metabolism of retinol toretinoic acidrdquo Journal of Biological Chemistry vol 278 no 38pp 36085ndash36090 2003

[34] G Elizondo J Corchero E Sterneck and F J GonzalezldquoFeedback inhibition of the retinaldehyde dehydrogenase geneALDH1 by retinoic acid through retinoic acid receptor 120572and CCAATenhancer-binding protein 120573rdquo Journal of BiologicalChemistry vol 275 no 50 pp 39747ndash39753 2000

[35] G Elizondo I M Medina-Dıaz R Cruz F J Gonzalez and LVega ldquoRetinoic acid modulates retinaldehyde dehydrogenase 1gene expression through the induction of GADD153-CEBP120573interactionrdquo Biochemical Pharmacology vol 77 no 2 pp 248ndash257 2009

[36] K Fujiwara M Kikuchi K Horiguchi et al ldquoEstrogen receptoralpha regulates retinaldehyde dehydrogenase 1 expression in ratanterior pituitary cellsrdquo Endocrine Journal vol 56 no 8 pp963ndash973 2009

[37] K Fujiwara F Maekawa M Kikuchi S Takigami T Yadaand T Yashiro ldquoExpression of retinaldehyde dehydrogenase(RALDH)2 and RALDH3 but not RALDH1 in the developinganterior pituitary glands of ratsrdquo Cell and Tissue Research vol328 no 1 pp 129ndash135 2007

[38] GWolf ldquoThe enzymatic cleavage of 120573-carotene still controver-sialrdquo Nutrition Reviews vol 53 no 5 pp 134ndash137 1995

[39] S Abu-Abed P Dolle D Metzger B Beckett P Chambonand M Petkovich ldquoThe retinoic acid-metabolizing enzymeCYP26A1 is essential for normal hindbrain patterning verte-bral identity and development of posterior structuresrdquo Genesand Development vol 15 no 2 pp 226ndash240 2001

[40] M A Leo S Iida and C S Lieber ldquoRetinoic acid metabolismby a system reconstituted with cytochrome P-450rdquo Archives ofBiochemistry and Biophysics vol 234 no 1 pp 305ndash312 1984

[41] MA Leo JM Lasker J L Raucy C-I KimM Black andC SLieber ldquoMetabolism of retinol and retinoic acid by human livercytochrome P450IIC8rdquoArchives of Biochemistry and Biophysicsvol 269 no 1 pp 305ndash312 1989

[42] R Quere A Baudet B Cassinat et al ldquoPharmacogenomicanalysis of acute promyelocytic leukemia cells highlightsCYP26cytochrome metabolism in differential all-trans retinoic acidsensitivityrdquo Blood vol 109 no 10 pp 4450ndash4460 2007

[43] J AWhite B Beckett-Jones Y-D Guo et al ldquocDNA cloning ofhuman retinoic acid-metabolizing enzyme (hP450RAI) identi-fies a novel family of cytochromes p450 (CYP26)rdquo Journal ofBiological Chemistry vol 272 no 30 pp 18538ndash18541 1997

[44] Y Zhang R Zolfaghari Reza and A C Ross ldquoMultiple retinoicacid response elements cooperate to enhance the inducibility ofCYP26A1 gene expression in liverrdquo Gene vol 464 no 1-2 pp32ndash43 2010

[45] Y Li Y Zhang R Li et al ldquoThe hepatic raldh1 expression iselevated in Zucker fatty rats and its over-expression introducedthe retinal-induced Srebp-1c expression in INS-1 cellsrdquo PLoSONE vol 7 no 9 Article ID e45210 2012

[46] R M Evans ldquoThe nuclear receptor superfamily a Rosetta stonefor physiologyrdquo Molecular Endocrinology vol 19 no 6 pp1429ndash1438 2005

[47] P Chambon ldquoA decade of molecular biology of retinoic acidreceptorsrdquo FASEB Journal vol 10 no 9 pp 940ndash954 1996

[48] D J Mangelsdorf and RM Evans ldquoThe RXR heterodimers andorphan receptorsrdquo Cell vol 83 no 6 pp 841ndash850 1995

[49] J E Balmer and R Blomhoff ldquoA robust characterization ofretinoic acid response elements based on a comparison of sitesin three speciesrdquo Journal of Steroid Biochemistry and MolecularBiology vol 96 no 5 pp 347ndash354 2005

[50] R Kurokawa J DiRenzo M Boehm et al ldquoRegulation ofretinoid signalling by receptor polarity and allosteric control ofligand bindingrdquo Nature vol 371 no 6497 pp 528ndash531 1994

[51] A Cvekl and W-L Wang ldquoRetinoic acid signaling in mam-malian eye developmentrdquo Experimental Eye Research vol 89no 3 pp 280ndash291 2009

[52] V Dupe M Davenne J Brocard et al ldquoIn vivo functional anal-ysis of the Hoxa-1 31015840 retinoic acid response element (31015840RARE)rdquoDevelopment vol 124 no 2 pp 399ndash410 1997

[53] A C Ross ldquoRetinoid production and catabolism role of dietin regulating retinol esterification and retinoic acid oxidationrdquoJournal of Nutrition vol 133 no 1 pp 291ndash296 2003

[54] T Moore and P D Holmes ldquoThe production of experimentalvitamin A deficiency in rats andmicerdquo Laboratory Animals vol5 no 2 pp 239ndash250 1971

[55] A C Ross and E H Harrison ldquoVitamin A and carotenoidsrdquoin Handbook of Vitamins D E McCormick R R Rucker J WSuttie et al Eds CRC Press Boca Raton Fla USA 4th edition2006

[56] A Chawta J J Repa R M Evans and D J MangelsdorfldquoNuclear receptors and lipid physiology opening the x-filesrdquoScience vol 294 no 5548 pp 1866ndash1870 2001

[57] C K Glass and M G Rosenfeld ldquoThe coregulator exchangein transcriptional functions of nuclear receptorsrdquo Genes andDevelopment vol 14 no 2 pp 121ndash141 2000

[58] A L Bookout Y Jeong M Downes R T Yu R M EvansandD JMangelsdorf ldquoAnatomical profiling of nuclear receptorexpression reveals a hierarchical transcriptional networkrdquo Cellvol 126 no 4 pp 789ndash799 2006

[59] B Mascrez M Mark W Krezel et al ldquoDifferential contribu-tions of AF-1 andAF-2 activities to the developmental functionsof RXR120572rdquo Development vol 128 no 11 pp 2049ndash2062 2001

[60] D Li T Li F Wang H Tian and H H Samuels ldquoFunctionalevidence for retinoid X receptor (RXR) as a nonsilent partner

ISRN Hepatology 15

in the thyroid hormone receptorRXR heterodimerrdquoMolecularand Cellular Biology vol 22 no 16 pp 5782ndash5792 2002

[61] F M Sladek W Zhong E Lai and J E Darnell Jr ldquoLiver-enriched transcription factor HNF-4 is a novel member ofthe steroid hormone receptor superfamilyrdquo Genes and Develop-ment vol 4 no 12 pp 2353ndash2365 1990

[62] K Yamagata H Furuta N Oda et al ldquoMutations in thehepatocyte nuclear factor-4120572 gene inmaturity-onset diabetes ofthe young (MODY1)rdquo Nature vol 384 no 6608 pp 458ndash4601996

[63] M Stoffel and S ADuncan ldquoThematurity-onset diabetes of theyoung (MODY1) transcription factor HNF4120572 regulates expres-sion of genes required for glucose transport and metabolismrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 24 pp 13209ndash13214 1997

[64] M Lehto P-O Bitzen B Isomaa et al ldquoMutation in the HNF-4120572 gene affects insulin secretion and triglyceride metabolismrdquoDiabetes vol 48 no 2 pp 423ndash425 1999

[65] G P Hayhurst Y-H Lee G Lambert J M Ward and F JGonzalez ldquoHepatocyte nuclear factor 4120572 (Nuclear receptor 2A1)is essential formaintenance of hepatic gene expression and lipidhomeostasisrdquo Molecular and Cellular Biology vol 21 no 4 pp1393ndash1403 2001

[66] U Roth K Jungermann and T Kietzmann ldquoActivation ofglucokinase gene expression by hepatic nuclear factor 4120572 inprimary hepatocytesrdquo Biochemical Journal vol 365 no 1 pp223ndash228 2002

[67] S Mandard R Stienstra P Escher et al ldquoGlycogen synthase2 is a novel target gene of peroxisome proliferator-activatedreceptorsrdquo Cellular and Molecular Life Sciences vol 64 no 9pp 1145ndash1157 2007

[68] F Rajas A Gautier I Bady S Montano and G MithieuxldquoPolyunsaturated fatty acyl coenzyme a suppress the glucose-6-phosphatase promoter activity bymodulating the DNA bindingof hepatocyte nuclear factor 4120572rdquo Journal of Biological Chemistryvol 277 no 18 pp 15736ndash15744 2002

[69] B Viollet A Kahn and M Raymondjean ldquoProtein kinase A-dependent phosphorylation modulates DNA-binding activityof hepatocyte nuclear factor 4rdquoMolecular and Cellular Biologyvol 17 no 8 pp 4208ndash4219 1997

[70] L Palanker J M Tennessen G Lam and C S Thum-mel ldquoDrosophila HNF4 regulates lipid mobilization and 120573-oxidationrdquo Cell Metabolism vol 9 no 3 pp 228ndash239 2009

[71] A Miura K Yamagata M Kakei et al ldquoHepatocyte nuclearfactor-4120572 is essential for glucose-stimulated insulin secretion bypancreatic 120573-cellsrdquo Journal of Biological Chemistry vol 281 no8 pp 5246ndash5257 2006

[72] R Bartoov-Shifman R Hertz H Wang C B Wollheim JBar-Tana and M D Walker ldquoActivation of the insulin genepromoter through a direct effect of hepatocyte nuclear factor4120572rdquo Journal of Biological Chemistry vol 277 no 29 pp 25914ndash25919 2002

[73] H Wang P Maechler P A Antinozzi K A Hagenfeldt andC B Wollheim ldquoHepatocyte nuclear factor 4120572 regulates theexpression of pancreatic 120573-cell genes implicated in glucosemetabolism and nutrient-induced insulin secretionrdquo Journal ofBiological Chemistry vol 275 no 46 pp 35953ndash35959 2000

[74] K Reue T Leff and J L Breslow ldquoHuman apolipoproteinCIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factorsrdquo Journal ofBiological Chemistry vol 263 no 14 pp 6857ndash6864 1988

[75] T Leff K Reue A Melian H Culver and J L BreslowldquoA regulatory element in the apoCIII promoter that directshepatic specific transcription binds to proteins in expressingand nonexpressing cell typesrdquo Journal of Biological Chemistryvol 264 no 27 pp 16132ndash16137 1989

[76] S N Lavrentiadou M Hadzopoulou-Cladaras D Kardassisand V I Zannis ldquoBinding specificity and modulation of thehuman apocIII promoter activity by heterodimers of ligand-dependent nuclear receptorsrdquo Biochemistry vol 38 no 3 pp964ndash975 1999

[77] T R Magee Y Cai M E El-Houseini J Locker and Y-JY Wan ldquoRetinoic acid mediates down-regulation of the 120572-fetoprotein gene through decreased expression of hepatocytenuclear factorsrdquo Journal of Biological Chemistry vol 273 no 45pp 30024ndash30032 1998

[78] A Qian Y Cai T R Magee and Y J Y Wan ldquoIdentificationof retinoic acid-responsive elements on the HNF1alpha andHNF4alpha genesrdquo Biochemical and Biophysical Research Com-munications vol 276 no 3 pp 837ndash842 2000

[79] H Nakshatri and P Chambon ldquoThe directly repeatedRG(GT)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites forRAR RXR HNF-4 and ARP-1 homo- and heterodimersrdquoJournal of Biological Chemistry vol 269 no 2 pp 890ndash9021994

[80] T Makita G Hernandez-Hoyos T H-P Chen H Wu E VRothenberg and H M Sucov ldquoA developmental transition indefinitive erythropoiesis erythropoietin expression is sequen-tially regulated by retinoic acid receptors andHNF4rdquoGenes andDevelopment vol 15 no 7 pp 889ndash901 2001

[81] T I Kambe J Tada-Kambe Y Kuge Y Yamaguchi-Iwai MNagao and R Sasaki ldquoRetinoic acid stimulates erythropoietingene transcription in embryonal carcinoma cells through thedirect repeat of a steroidthyroid hormone receptor responseelement half-site in the hypoxia-response enhancerrdquo Blood vol96 no 9 pp 3265ndash3271 2000

[82] F-J Lin J Qin K Tang S Y Tsai and M-J Tsai ldquoCoup drsquoEtatan orphan takes controlrdquo Endocrine Reviews vol 32 no 3 pp404ndash421 2011

[83] L-H Wang S Y Tsai R G Cook W G Beattie M-J Tsaiand BW OrsquoMalley ldquoCOUP transcription factor is a member ofthe steroid receptor superfamilyrdquoNature vol 340 no 6229 pp163ndash166 1989

[84] X Leng A J Cooney S Y Tsai and M-J Tsai ldquoMolecularmechanisms of COUP-TF-mediated transcriptional repressionevidence for transrepression and active repressionrdquo Molecularand Cellular Biology vol 16 no 5 pp 2332ndash2340 1996

[85] L Li X Xie J Qin et al ldquoThe nuclear orphan receptorCOUP-TFII plays an essential role in adipogenesis glucosehomeostasis and energy metabolismrdquo Cell Metabolism vol 9no 1 pp 77ndash87 2009

[86] F A Pereira Q Yuhong G Zhou M-J Tsai and S YTsai ldquoThe orphan nuclear receptor COUP-TFII is required forangiogenesis and heart developmentrdquo Genes and Developmentvol 13 no 8 pp 1037ndash1049 1999

[87] N Takamoto I Kurihara K Lee F J DeMayo M-J Tsai andS Y Tsai ldquoHaploinsufficiency of chicken ovalbumin upstreampromoter transcription factor II in female reproductionrdquoMolec-ular Endocrinology vol 19 no 9 pp 2299ndash2308 2005

[88] P Zhang M Bennoun C Gogard et al ldquoExpression of COUP-TFII in metabolic tissues during developmentrdquo Mechanisms ofDevelopment vol 119 no 1 pp 109ndash114 2002

16 ISRN Hepatology

[89] Z Xu S Yu C-H Hsu J Eguchi and E D Rosen ldquoTheorphan nuclear receptor chicken ovalbumin upstream pro-moter-transcription factor II is a critical regulator of adipogene-sisrdquoProceedings of theNationalAcademy of Sciences of theUnitedStates of America vol 105 no 7 pp 2421ndash2426 2008

[90] P Bardoux P Zhang D Flamez et al ldquoEssential role of chickenovalbumin upstreampromoter-transcription factor II in insulinsecretion and insulin sensitivity revealed by conditional geneknockoutrdquo Diabetes vol 54 no 5 pp 1357ndash1363 2005

[91] G Achatz B Holzl R Speckmayer C Hauser F Sandhoferand B Paulweber ldquoFunctional domains of the human orphanreceptor ARP-1COUP-TFII involved in active repression andtransrepressionrdquo Molecular and Cellular Biology vol 17 no 9pp 4914ndash4932 1997

[92] S A Kliewer K Umesono R A Heyman D J MangelsdorfJ A Dyck and R M Evans ldquoRetinoid X receptor-COUP-TFinteractionsmodulate retinoic acid signalingrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol89 no 4 pp 1448ndash1452 1992

[93] A J Cooney S Y Tsai BW OrsquoMalley andM-J Tsai ldquoChickenovalbumin upstreampromoter transcription factor (COUP-TF)dimers bind to different GGTCA response elements allowingCOUP-TF to repress hormonal induction of the vitamin D3thyroid hormone and retinoic acid receptorsrdquo Molecular andCellular Biology vol 12 no 9 pp 4153ndash4163 1992

[94] SW Kruse K Suino-Powell X E Zhou et al ldquoIdentification ofCOUP-TFII orphannuclear receptor as a retinoic acid-activatedreceptorrdquo PLoS Biology vol 6 no 9 Article ID e227 2008

[95] J P Berger T E Akiyama and P T Meinke ldquoPPARs thera-peutic targets for metabolic diseaserdquo Trends in PharmacologicalSciences vol 26 no 5 pp 244ndash251 2005

[96] JM Peters andF J Gonzalez ldquoSorting out the functional role(s)of peroxisome proliferator-activated receptor-120573120575 (PPAR120573120575)in cell proliferation and cancerrdquo Biochimica et Biophysica Actavol 1796 no 2 pp 230ndash241 2009

[97] A Tenenbaum and E Fisman ldquoBalanced pan-PPAR activatorbezafibrate in combination with statin comprehensive lipidscontrol and diabetes preventionrdquo Cardiovascular Diabetologyvol 11 no 1 article 140 2012

[98] O Braissant F Foufelle C Scotto M Dauca and W WahlildquoDifferential expression of peroxisome proliferator-activatedreceptors (PPARs) tissue distribution of PPAR-120572 -120573 and -120574 inthe adult ratrdquo Endocrinology vol 137 no 1 pp 354ndash366 1996

[99] H Higashiyama A N Billin Y Okamoto M Kinoshita andS Asano ldquoExpression profiling of Peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues usingtissue microarrayrdquo Histochemistry and Cell Biology vol 127 no5 pp 485ndash494 2007

[100] P S Jones R Savory P Barratt et al ldquoChromosomal local-isation inducibility tissue-specific expression and strain dif-ferences in three murine peroxisome-proliferator-activated-receptor genesrdquo European Journal of Biochemistry vol 233 no1 pp 219ndash226 1995

[101] S A Kliewer B M Forman B Blumberg et al ldquoDifferentialexpression and activation of a family of murine peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no15 pp 7355ndash7359 1994

[102] E E Girroir H E Hollingshead P He B Zhu G H Perdewand J M Peters ldquoQuantitative expression patterns of peroxi-some proliferator-activated receptor-120573120575 (PPAR120573120575) protein in

micerdquo Biochemical and Biophysical Research Communicationsvol 371 no 3 pp 456ndash461 2008

[103] P Escher O Braissant S Basu-Modak L Michalik W Wahliand B Desvergne ldquoRat PPARs quantitative analysis in adult rattissues and regulation in fasting and refeedingrdquo Endocrinologyvol 142 no 10 pp 4195ndash4202 2001

[104] D Auboeuf J Rieusset L Fajas et al ldquoTissue distributionand quantification of the expression of mRNAs of peroxi-some proliferator-activated receptors and liver X receptor-120572 inhumans no alteration in adipose tissue of obese and NIDDMpatientsrdquo Diabetes vol 46 no 8 pp 1319ndash1327 1997

[105] N ShawM Elholm andN Noy ldquoRetinoic acid is a high affinityselective ligand for the peroxisome proliferator-activated recep-tor 120573120575rdquo Journal of Biological Chemistry vol 278 no 43 pp41589ndash41592 2003

[106] G Wolf ldquoRetinoic acid as cause of cell proliferation or cellgrowth inhibition depending on activation of one of twodifferent nuclear receptorsrdquoNutrition Reviews vol 66 no 1 pp55ndash59 2008

[107] T T Schug D C Berry N S Shaw S N Travis and N NoyldquoOpposing effects of retinoic acid on cell growth result fromalternate activation of two different nuclear receptorsrdquo Cell vol129 no 4 pp 723ndash733 2007

[108] D C Berry and N Noy ldquoAll-trans-retinoic acid repressesobesity and insulin resistance by activating both peroxisomeproliferation-activated receptor 120573120575 and retinoic acid receptorrdquoMolecular and Cellular Biology vol 29 no 12 pp 3286ndash32962009

[109] D C Berry D DeSantis H Soltanian C M Croniger andN Noy ldquoRetinoic acid upregulates preadipocyte genes to blockadipogenesis and suppress diet-induced obesityrdquo Diabetes vol61 no 5 pp 1112ndash1121 2012

[110] M G Borland C Khozoie P P Albrecht et al ldquoStableover-expression of PPAR120573120575 and PPAR120574 to examine receptorsignaling in human HaCaT keratinocytesrdquo Cellular Signallingvol 23 no 12 pp 2039ndash2050 2011

[111] S E OrsquoSullivan and D A Kendall ldquoCannabinoid activationof peroxisome proliferator-activated receptors potential formodulation of inflammatory diseaserdquo Immunobiology vol 215no 8 pp 611ndash616 2010

[112] Z C Yan D Y Liu L L Zhang et al ldquoExercise reduces adiposetissue via cannabinoid receptor type 1 which is regulated byperoxisome proliferator-activated receptor-120575rdquo Biochemical andBiophysical Research Communications vol 354 no 2 pp 427ndash433 2007

[113] J D McGarry ldquoWhat if Minkowski had been ageusic Analternative angle on diabetesrdquo Science vol 258 no 5083 pp766ndash770 1992

[114] TMoore ldquoVitaminA and carotene the vitaminA reserve of theadult human being in health and diseaserdquo Biochemical Journalvol 31 no 1 pp 155ndash164 1937

[115] GWolfMD Lane and B C Johnson ldquoStudies on the functionof vitamin A in metabolismrdquo Journal of Biological Chemistryvol 225 no 2 pp 995ndash1008 1957

[116] Y Zhang R Li Y Li W Chen S Zhao and G Chen ldquoVitaminA status affects obesity development and hepatic expression ofkey genes for fuel metabolism in Zucker fatty ratsrdquoBiochemistryand Cell Biology vol 90 no 4 pp 548ndash557 2012

[117] M Singh V N Singh and T A Venkitasubramanian ldquoEarlyeffects of feeding excess vitamin A hepatic glycogen bloodlactic acid plasma nefa and glucose tolerance in ratsrdquo LifeSciences vol 7 no 5 pp 239ndash247 1968

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Hepatology 7

[130 131] The mechanisms by which the upstream and thedownstream promoters are selectively activated in differentcells have not been revealedThe temporal and special controlof the promoter selectionmust be determined by signals fromdifferentiation and development processes

The upstream and downstream promoters are activatedbased on the hormonal and nutritional conditions of thesubject For example the hepatic but not the pancreatic 120573-cell Gck expression is reduced while fasting and increasedwhile refeeding [130] In the rat liver insulin and glucagonrespectively induce and inhibit the expression of GckmRNA[133ndash135] A long-standing question in the field is the insulin-responsive element (IRE) responsible for the insulin-inducedhepaticGck expression Using the reporter gene constructs tostudy insulin-induced Gck promoter activation has not beensuccessful For example a reporter gene construct containinga fragment of 55 kb hepatic Gck promoter failed to showany response to insulin treatment in rat primary hepatocytes[136] This suggests that the IRE of the hepatic Gck mightbe in an area not included in this 55 kb promoter fragmentAlternatively the unresponsiveness to insulin of the reportergene constructs in the experimental settings could be due tothe short-lived signal from insulin for Gck transcription aswe have shownpreviously [137] Interestingly the hepatocyte-specific enhancer region that controls the activation of liver-specific promoter has been located in the region from minus1003to minus707 relative to the transcription initiation site in primaryrat hepatocytes By contrast this region acts as a silencer inFTO-2B hepatoma cells and has no effects on insulinomacells [138] Further studies are needed to identify the insulin-responsive element in the hepatic Gck promoter

The direct effects of RA on the expression of Gck mRNAin primary rat hepatocytes have been studied Previouslyothers have shown that all-trans RA induced Gck expressionin primary rat hepatocytes However nonadditive effect ofRA on insulin-induced Gck expression was observed [139140] Recently we have shown that retinoids synergized withinsulin to induce Gck expression in primary rat hepatocytes[137] We have observed that all-trans retinol retinal and RAare able to synergize with insulin to induce Gck expressionprobably via the activation of RARRXR in primary rat hepa-tocytes In addition VA status also controls the expression ofhepatic Gck expression [137] The levels of Gck mRNA [116]and its activity [137] in the liver of VAD rats are lower thanthose of VA-sufficient (VAS) controls In addition a singletreatment of RA increases the hepatic Gck expression in rats[137]

23 The Effects of Animal VA Status and Retinoids onPck1 Gene Expression The plasma glucose homeostasis isachieved through its dietary intake and production fromendogenous noncarbohydrate sources During fasting glu-cose is generated via gluconeogenesis The cytosolic form ofphosphoenolpyruvate carboxykinase (PEPCK-C EC41132)which catalyzes the conversion of oxaloacetate into phos-phoenolpyruvate in the presence of GTP [141] has beenconsidered to be the first rate-limiting enzyme of gluconeoge-nesisThe expression of PEPCK-C gene (Pck1) and its activity

have been detected in the liver kidney adipose tissues andsome other tissues [141ndash143] Other than gluconeogenesisPEPCK-C activity has been considered to be responsible forglyceroneogenesis and cataplerosis [144] Since no allostericregulator of PEPCK-C has been identified its activity isprimarily controlled by the level of Pck1mRNA [141ndash143]

The transcription of hepatic Pck1 is regulated by hor-monal and nutritional stimuli In the liver fasting diabetescarbohydrate-free diets and high-fat diets increase Pck1 geneexpression whereas refeeding insulin treatment and high-carbohydrate diets decrease Pck1 gene expression Glucagonglucocorticoids thyroid hormone and RA induce hepaticPck1 expression while insulin and glucose inhibit it [145]

The transcription regulation of Pck1 has been studiedextensively [142 143] The protein-binding sites at the prox-imal region of rat Pck1 promoter have been determined byDNase I footprinting assays [146 147] Multiple regulatoryelements including distal proximal cyclic AMP-responsiveelement (CRE) [148] have been identified Proteins in ratliver nuclear extracts can interact with the two CREs andsix additional binding sites (P1 to 6) [142] The transcrip-tion factors that bind to these sites include HNF4120572 [149]glucocorticoid receptor [148 150ndash153] RAR [154ndash157] TR[154 158] LXR [159] COUP-TF [149] the Forkhead familyof transcription factors [160] CEBP and cAMP regulatoryelement-binding (CREB) protein [161] and SREBP-1c [162163] Additionally transcription coactivators such as CREB-binding protein (CBP) [164] steroid receptor coactivator 1(SRC1) [165] and peroxisome proliferator-activated receptorgamma coactivator-1-alpha (PGC-1120572) [166] also participatein the regulation of hepatic Pck1 gene expression

Using reporter gene assays and hepatoma cells twoRAREs have been identified in the hepatic Pck1 promoter[154 155 167]WhenPEPCKbovine growth hormone (bGH)transgenic mouse strains are used VA deficiency causes thereduction of the transgenersquos transcription [167]The RARE1 isconsidered to be important for mediating the RA-regulatedPck1 expression in the mouse liver [157] In mice VA statusaffects the association of RNApolymerase II and histone codeof Pck1 promoter [168 169] Later on these RAREs have beenshown to bind toHNF4120572 RXR120572 RAR120572 PPAR120572 and COUP-TFII [170]

In an attempt to study the lipophilic molecules that affectinsulin-regulated gene expression in primary rat hepatocyteswe have obtained lipophilic extract (LE) from the rat liverMyoriginal study has shown that this LE induces Pck1 expressionand attenuates insulin-mediated suppression of Pck1 tran-scription in primary rat hepatocytes [171] Interestingly thesame LE synergizes with insulin to induce Gck expression inthe same cells [137]The activemolecules in the LE are retinoland retinal [137] We have shown that retinol retinal andRA all can affect insulin-suppressed Pck1 expression [172]In rat primary hepatocytes the proximal one of the twoRAREs in the rat Pck1 promoter [154ndash156] is responsiblefor mediating the retinoid effects [172] The expression ofhepatic Pck1mRNA in rats seems to respond to VA deficiencydifferently from that in mice We have shown that the hepaticPck1mRNA level in the Zucker lean (ZL) rats is not reduced

8 ISRN Hepatology

Hepatocyte

Induction

Induction

Induction

1 2

Gck

Pck1

Cell membraneCytosol

RA RA

RARESynergy

Signalcascade Insulin

AttenuationNuclear

membrane NucleusRAREs

Inhibitio

n

Figure 2 RA synergizes with insulin to induce Gck expressionand attenuates insulin-suppressed Pck1 expression RA inducesthe expression levels of Gck and Pck1 via the activation of bothRARRXR (the oval dimmers on the RAREs) in the absenceof insulin Insulin alone stimulates the expression of Gck andsuppresses the expression of Pck1 In the presence of both insulinand RA the expression of Gck is further increased (synergy) Onthe other hand the insulin-mediated suppression of Pck1 expressionis attenuated This is because RA still induces Pck1 expressionvia activation of RAR in the presence of insulin Therefore Pck1transcript level in the RA + insulin group is higher than that in theinsulin group (attenuation)

in VA-deficient state [116] VA deficiency only reduces thehepatic Pck1mRNA in the Zucker fatty (ZF) rats [116]

It is important to note that the respective activities of GKand PEPCK-C are induced in different physiological condi-tions For example insulin induces Gck and suppresses Pck1expression as shown in Figure 2 In primary rat hepatocytesactivation of either RARs or RXRs by RA is sufficient toinduce the expression of both Pck1 [172] and Gck [137] How-ever activation of RAR potentiates (for the insulin-mediatedinduction of Gck expression) and attenuates (for the insulin-mediated suppression of Pck1 expression) insulin actionsat the same time in the same hepatocytes For Gck RA-mediated activation of RARs and RXRs can be potentiated byinsulin [137] which results in the synergy For Pck1 only RA-activated RXRs but not RARs are inhibited by insulin whichresults in the attenuation [172] This causes the production ofmore Pck1 mRNA in the presence of RA than in the absenceof it even in the insulin-suppressed state It indicates that themechanisms of RA-mediated activation of RARs and RXRsprobably depend on the promoter context or the isoformsassociated with the promoters of their downstream genesin the presence of insulin Therefore the roles of retinoidsin hepatic glucose metabolism deserve further investigationespecially the roles of the interactions between retinoidsand insulin signaling pathways in the regulation of genetranscription

24 Role of RBP4 in Insulin Resistance Plasma VA is boundto RBP4 which is mainly produced in the liver [13] TheRbp4 mRNA is also expressed to a certain extent in adipose

tissues and kidney [13] In the plasma retinol-RBP4 complexis associated with transthyretin (TTR) a process to increasethe size of the holo-RBP4-TTR complex to reduce the lossduring renal filtration [173]

Recently the plasma RBP4 has been suggested to playroles in metabolic homeostasis It has been reported thatinsulin-resistant human subjects and animals have higherplasma RBP4 levels than normal ones due to its elevatedproduction from adipose tissues [174] In mice RBP4administration has been shown to reduce insulin sensitivityand increase the expression levels of hepatic gluconeogenicgenes such as Pck1 and the catalytic subunit of glucose 6-phosphatase (G6pc) [175] Additionally reduction of plasmaretinol and RBP levels has been reported in type 1 diabeticpatients [176] and in streptozotocin- (STZ-) induced diabeticrats [177] Rbp4 knockout mice have improved insulin sen-sitivity [175] The treatment fenretinide a synthetic retinoidderivative that disrupts the association of RBP4 and TTRimproves insulin sensitivity in HFD-induced obese mice[175]

When a compound specifically developed to disrupt theRBP4 and TTR interaction was used to treat mice it suc-cessfully disrupted the formation of RBP4-TTR complex andcaused the reduction of plasma RBP4 level [178] Howeverthe reduction of plasma RBP4 level did not result in animprovement of insulin sensitivity [178] In addition theimprovement of insulin sensitivity in Rbp4 knockout micecould not be observed in this study [178] Therefore the ele-vation of insulin sensitivity in mice treated with fenretinideis probably due to a mechanism other than the disruption ofRBP-TTR complex and reduction of plasma RBP4 levels

3 Roles of VA in FA and TG Metabolism

FAs are needed for many aspects of cellular functions fromsignal transduction to energy production The continuoussurvival of a given cell depends on the constant energysupplies from the environment or storage sources Thestorage of FA in the form of TG ensures the constant energysupply in a cell or organism for a prolonged period oftime when environment energy is limited In animals thehomeostasis of FA and TG is dynamically regulated by theliver and the adipose tissues in response to nutritional andhormonal stimuli [179 180] During fasting or starvation FAsare released from adipose depots after lipolysis and oxidizedin the liver and muscle for energy production [181] Afterrefeeding dietary and newly synthesized FAs are convertedto TGs for the storage in the adipose tissues [182] On theother hand the altered regulation of this system may causeproblems For example the excessive synthesis and storage ofFAs in the form of TGs can cause the development of obesityand other metabolic diseases

31 The Effects of VA Status on the Body Fat and Plasma LipidProfile VA was first recognized as a dietary lipophilic factorwhich was essential to support the normal growth of labanimals [3 4] Subsequently it was observed that along withthe reduction of body mass the VAD rats that had been fed

ISRN Hepatology 9

aVADdiet at weaning (21 days old) formore than 9weeks hadreduction of carcass fat but not cholesterol content [183] Onthe other hand this reduction of body fat was not observedin the rats of the pair-feeding group which were given thesame amount of a VAS diet in weight and calories as theone consumed by the VAD rats [183] These results indicatethat the reduction of food intake alone could not be used toexplain the depletion of body fat in the VAD rats

The VA status also seems to affect the hepatic expressionof apo AI mRNA The expression of hepatic apo AI hasbeen shown to be sensitive to VA status [184] When theLewis strain rats develop VA deficiency the expression levelof hepatic but not intestinal apo AI mRNA is elevated Thisinduction is dropped upon single dosage of RA treatment[184] On the other hand in the intestine and liver of VA-deficient Wistar rats both all-trans RA and 9-cis RA caninduce apo AI mRNA levels [185] The same treatment canonly induce the mRNA level of apo CIII in the intestine butnot in the liver [185] In humans the plasma VA levels arepositively correlated with the elevations of proteins of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiapatients [186]

When male Wistar rats were fed a VAD diet for 3 monthsafter weaning (21 days old) they had lower plasma TGs andcholesterol levels than the control ones fed a VAS diet [187]When the hepatic synthesis of FAs and phospholipids wasanalyzed in the liver slices the incorporations of [14C]cholineinto phosphatidylcholine and [14C]acetate into FAs were alsoreduced in the VAD rats compared with their VAS controls[187] The VAD rats had lower activities and mRNA levels ofacetyl-CoA carboxylase but higher activity and mRNA levelof carnitine palmitoyltransferase-I than VAS rats had [187]These results demonstrate that there is a reduction of hepaticfatty acid synthesis along with an induction of hepatic fattyacid oxidation in the liver of VAD rats

My lab has conducted experiments and shown that VAstatus affects the obesity development in ZF rats and controlsplasma TG levels in ZL and ZF rats [116] ZF rats a ratmodel of obesity development [188] develop obesity dueto a missense mutation in the extracellular domain of allleptin receptor isoforms [189ndash191] They have been used forthe studies of obesity insulin resistance and other aspectsof metabolic diseases [192 193] We have analyzed growthplasma parameters and expression levels of hepatic genes ofmale ZL and ZF rats fed a VAD or a VAS diet at weaning(21 days of age) for 8 weeks Body masses of ZL and ZF ratsfed the VAD diet are lower than those of their correspondingcontrols fed the VAS diet at the end of the feeding periodThe VAD ZL or ZF rats begin to take less food than the VASones after five weeks on the diet The VAD ZL or ZF rats havelower plasma glucose TG insulin and leptin levels than theircorresponding VAS rats have The liver glycogen content netweights of epididymal fat and liver and fat-to-body massratio (ZL only) in the VAD rats are also lower than those inthe VAS ones [116] This demonstrates that VA status affectsplasma TG levels in both ZF and ZL rats and the obesitydevelopment in ZF rats This phenomenon may be caused by

the combination of VA deficiency and hypoinsulinemia sinceinsulin secretion is impaired in the VAD rats [194]

32 The Development of Hypertriglyceridemia inPatients Receiving Retinoic Acid-Based Treatments

321 The Uses of RA-Based Medicines in Clinic RA-basedmedicines tretinoin (all-trans RA) isotretinoin (13-cis RA)and alitretinoin (9-cis RA) have been used in clinic to treatdiseases such as acute promyelocytic leukemia and skindisorders [11] In fact isotretinoin has been widely used totreat severe acne Early clinical observations indicate that themedical use of isotretinoin in human subjects results in theelevation of their plasma TG levels [195ndash197] A significantportion of patients with acne receiving isotretinoin treatmentdeveloped hypertriglyceridemia [9 10] In addition thesystemic administration of isotretinoin in patients with acneresulted in the elevation of plasma levels of alanine amino-transferase (ALT) and aspartate aminotransferase (AST)indicating the liver damage [198]The hypertriglyceridemia isalso associated with reduced insulin sensitivity and elevatedTG in the very-low-density lipoprotein (VLDL) fraction[195] The treatment of all-trans RA resulted in body massgain and hypertriglyceridemia in patients with acute promye-locytic leukemia [199 200] Moreover RA treatment alsoraises plasma TG levels in rats [201ndash203]

322 The Mechanism of RA-Mediated Hypertriglyceridemiain Patients Apo CIII is produced from liver and consideredan inhibitor of LPL activity [204] Mice with Apoc3 geneknockout have hypotriglyceridemia and enhanced in vivoVLDL-TG clearance [205] On the other hand transgenicmice with overexpression of apo CIII develop hypertriglyc-eridemia [206] The RA-induced hypertriglyceridemia hasbeen attributed to RA-induced apo CIII expression

In healthy human subjects isotretinoin treatment causesa rise of plasma apo CIII protein level [207]This is caused bythe induction of Apoc3 mRNA via the activation of RXR ata RARE in its promoter [207] The plasma TG levels in ratstreated with RXR-specific agonist (LG100268) are inducedrapidly and constantly [208] This results in the reducedactivity of LPL in the heart and skeletal muscle of thoseanimals [208] The RARE is identified in the C3P regionwhich controls the hepatic specific expression of Apoc3 gene[75] Interestingly the same site is also considered to beresponsible for mediating the effects of HNF4120572 and COUP-TFII onApoc3 gene expression [209]The expression ofApoc3seems to be regulated differently by the C3P-binding proteins[75]

It is worth to note that insulin suppresses Apoc3 mRNAexpression in STZ-induced diabetic mice [210] In additionthe activation of RXR by LG100268 treatment induces insulinsensitivity and reduces TG levels in obese and diabetic mice[211] The understanding of the regulatory mechanism thatintegrates hormonal and nutritional signals at the regulatorysites such as C3P in Apoc3 promoter will shed some lightson the regulation of hepatic lipid homeostasis It will also

10 ISRN Hepatology

provide a novel target for the treatment of the RA-inducedhypertriglyeridemia

323 The Effects of RA Treatment on Obesity Developmentin Mice Interestingly the RA administration in rodentscauses reduction of body mass as summarized in [212] Thiskind of reduction of body mass has been associated withenhancement of insulin sensitivity in genetic [213] or DIOmice [108] The mechanisms of RA-mediated attenuation ofinsulin resistance have been thought to be the induction ofenergy expenditure through PPAR120573120575 activation [108] andthe inhibition of adipogenesis throughRXR120574 activation [109]On the other hand retinol can be metabolized in adipose tis-sues [214]Themice with deletion ofRaldh1 gene (Raldh1minusminus)have elevated retinal in their adipose tissues and are resistantto diet-induced obesity and insulin resistance [26] This hasbeen attributed to the suppression of adipogenesis by retinal-inhibited activation of PPAR120574 and RXR [26] It is interestingto note that either retinal or RA can inhibit the adipogenesisand cause the improvement of insulin sensitivity in micebased on these studies

33 Roles of VA and Retinoids in the Regulation of HepaticLipogenic Gene Expression Insulin resistance diabetes andother metabolic abnormalities are associated with profoundchanges of hepatic lipid and glucose metabolismThis can beattributed at least in part to the altered expression of genesinvolved in glucose and lipid metabolism [215] The hepaticlipogenesis contributes to the homeostasis of FAs and TGs

331 The Regulation of Hepatic Srebp-1c Expression by VAStatus and Retinoids Treatment Insulin plays an essentialrole in the hepatic FA synthesis It has been known for a whilethat insulin is needed for the glucose usage for lipogenesis andCO2production in the liver [216] The hepatic FA synthesis

rises sharply and continuously after rats are fasted and thenrefed a high-carbohydrate diet [217] The amount of fattyacid synthase (FAS) is induced in normal rats refed a high-carbohydrate diet after fasting and in STZ-induced diabeticrats after insulin administration [218] In the insulin-deficientrats the induction of FAS after refeeding occurs only wheninsulin injection is injected [219] a process attributed to theinduction of FAS gene (Fas) [220 221]

The transcription of hepatic Fas is controlled by a tran-scription factor named SREBP-1c [222] In the liver-specificSrebp-1c knockoutmouse liver the induction of Fas and otherlipogenic genes by refeeding after fasting is blunted [223]Interestingly insulin also specifically induces the Srebp-1cexpression in the liver [224] via two liver X receptor elements(LXREs) and one sterol-responsive element (SRE) [225]However in liver-specific insulin receptor knockoutmice theinduction of hepatic Srebp-1c by refeeding largely remainedunchanged [226] This suggests that nutrient-derived signalsmay activate downstream of insulin receptor signaling path-way to regulate Srebp-1c expression and hepatic lipogenesis[226]

As stated in the previous section my research group hasobserved that the VAD ZL and ZF rats have lower plasma TG

levels than their VAS controls [116] This is accompanied bythe reduction of the hepatic expression of Srebp-1cmRNA inVA-deficient animals [116] My research group has reportedfor the first time that retinoids synergize with insulin toinduce the expression of Srebp-1c in primary rat hepatocytes[227] Further analysis of the Srebp-1c promoter reveals thatthe previous identified LXREs responsible for mediatinginsulin-induced Srebp-1c expression are also RAREs [227]These observations show that retinoids (nutritional) andinsulin (hormonal) signals converge to regulate the FAsynthesis in the liver

332 The Effects of VA Catabolism on the Regulation of Srebp-1c Expression in Primary Rat Hepatocytes More recentlyretinoids have been proposed to play roles in glucose and lipidmetabolism and to maintain energy homeostasis [228 229]VA (retinol) is reversibly converted into retinal and retinalis irreversibly converted into RA [23] Retinal the precursorof RA production is able to synergize with insulin to inducethe Srebp-1c expression in primary rat hepatocytes [227]This suggests that the dynamic production of RA influencesthe expression of hepatic lipogenic genes It has led us toinvestigate the roles of RA production in the insulin-resistantanimals

In the liver of the Raldh1minusminus mice RA production isreduced in response to a load of retinol [230] The Raldh1minusminusmice are resistant to the development of obesity and insulinresistance after being fed an HFD [26] This is attributed tothe elevation of retinal content due to the lack of conversionof retinal to RA in the adipose tissues of the Raldh1minusminusmice Additionally the liver of the Raldh1minusminus mice hasaltered regulation of the genes for gluconeogenesis andsignificantly attenuated hepatic TG synthesis indicating theimportant role of hepatic VAmetabolism in glucose and lipidhomeostasis [231]

The hepatic expression levels of RALDH1 and RALDH2are induced in mice fed a high-cholesterol diet [232] SREsare located in the promoters of these two genes whichare induced by SREBP-1c overexpression The expression ofSrebp-1c is induced by the oxysterols derived from the high-cholesterol diet [232] This research work demonstrates theinteraction of cholesterol and RA metabolism in the liver Inaddition it has been shown that the level of Raldh1mRNA iselevated in the kidney of dbdb mice [233] Both dbdb miceand ZF rats develop obesity due to the mutation of leptinreceptor [234]

In an attempt to understand the roles of VA metabolismin the states of metabolic diseases we have compared theexpression levels of enzymes responsible for the productionof retinal and RA in the freshly isolated and cultured primaryhepatocytes from ZL rats and ZF rats [45] We have foundthat in the primary rat hepatocytes the enzymes responsiblefor the conversions of retinol to retinal and from retinal toRA are most likely RDH2 and RALDH1 respectively Theexpression levels of Raldh1 mRNA and its protein are higherin hepatocytes from ZF rats than in those from ZL rats[45] When overexpressed RALDH1 introduces the retinal-mediated induction of Srebp-1c in INS-1 cells which do not

ISRN Hepatology 11

respond to retinal in our previous study [227] These resultsindicate that insulin-resistant animals such as ZF rats mayhave alterations in retinoids metabolism

Thus we have hypothesized that the change of RAproduction from the oversupply of dietary VA due to thehyperphagia of ZF rats results in higher Srebp-1c expressionin ZF hepatocytes [45] The elevated SREBP-1c expressioncan further induceRaldh1 expression to create a feed-forwardmechanism that could be one of the reasons responsible forthe increased lipogenesis in the liver of ZF rats All of theseobservations indicate the potential roles of RA metabolismin the development of obesity and insulin resistance whichdeserves to be further studied

4 VArsquos Roles in Mediating Hepatic InsulinAction and Insulin Resistance

41 Insulin and Its Signal Transduction The insulin moleculeis made of two chains linked by one intra- and one interchaindisulfide bonds [235] The insulin receptor is a transmem-brane and heterotetramer tyrosine kinase receptor (two 120572and two 120573 subunits) linked by disulfide bonds as well [236]The binding of insulin to its receptor causes conformationchanges and transphosphorylation of the 120573-subunit tyrosinekinase [237 238] which initiates the signal transduction[239] Protein-protein interactions are involved in the trans-duction of insulin signalThe signal is transduced bymultiplecomponents in a complex network containing cascades ofkinases and phosphatases [240 241] The first intracellularcomponents mediating insulin signals are insulin recep-tor substrates (IRSs) protein molecules phosphorylated byinsulin receptor 120573-subunit and mediating insulin signals[242]

The insulin signal event is further amplified byphosphatidylinositide 3-kinases (PI3K)protein kinaseB (PKBAkt) pathway and GRB2mitogen-activated proteinkinase (MAPK) pathway [243ndash245] Another serinethre-onine kinase that can be activated by PI3K is the atypicalprotein kinase C [246] Human liver expresses severalprotein-tyrosine phosphatases (PTPs) [247] Okadai acid aninhibitor of protein phosphatase type 2A and type 1 inhibitsglycogen synthesis and insulin-stimulated Gck expression inprimary rat hepatocytes indicating that dephosphorylationmechanism may also participate in mediating insulinsignaling [248] These components are shared by insulin-likegrowth factor (IGF) receptor and involved in mediatinginsulin and IGF signals [249]

42 Metabolic Diseases and Insulin Resistance The rise ofthe number of people with one or more metabolic diseasessuch as obesity and diabetes in the world has become apublic health problem [250] The interactions of genetic andenvironmentalnutritional factors may be responsible for thecurrent rise of metabolic diseases The long evolutionaryprocess has equipped human and animal bodieswith a varietyof regulatory mechanisms controlling these interactions [251252] Human diets contain not only energy derived frommacronutrients but also micronutrients and other factors

which may influence the metabolic outcomes The roles ofindividual micronutrients in the development of metabolicdiseases are still unrevealed

One common property of human obesity and NIDDMis insulin resistance in which a given amount of insulinproduces less than normal physiological responses Dietaryfactors and manipulations have been considered to play arole in the development of insulin resistance in humans andanimals For example feeding an HFD to young and insulin-sensitive subjects for two days causes the development ofglucose intolerance [253] In the skeletal muscle of rats fedan HFD for 8 weeks the insulin-induced glucose uptakeis impaired [254] FFAs have been considered the factorsresponsible for HFD-induced leptin and insulin resistance[255ndash257]

43 Hepatic Insulin Resistance and Vicious Cycle The liverplays an essential role in the control of glucose andlipid homeostasis It coordinately regulates the processesin responses to nutritional and hormonal stimuli Insulinplays a major role in directing the liverrsquos metabolic status[258] which is partially attributed to the regulation of theexpression of genes involved in hepatic glucose and lipidmetabolism [215 259]

Insulin controls the expression of a variety of genesinvolved in glycolysis glycogenesis and lipogenesis andgluconeogenesis in the liver [145] Generally hepatic lipidand glucose metabolism is altered with the development ofinsulin resistance in obesity and NIDDM [258] This canbe reflected in the expression of insulin-regulated hepaticgenes for glucose and FA metabolism When the liver isinsulin sensitive insulin stimulates lipogenesis and inhibitsgluconeogenesis For example to regulate hepatic glucosehomeostasis insulin increases the expression of Gck gene[119 120] and Srebp-1c [224] a family member of SREBPswhich regulate the hepatic cholesterol and FA biosynthesisand their homeostasis [260] It suppresses the expressionof Pck1 [142] and G6pc [145] which control the first andlast steps of gluconeogenesis respectively When the liver isinsulin resistant insulin no longer inhibits gluconeogenesisHowever the liver still keeps the elevated lipogenesis Theelevated FA biosynthesis in the insulin-resistant state furtherfacilitates insulin secretion from pancreatic 120573-cells whichprobably enhances lipogenesis and results in a vicious cycle[113 261] The coexistence of the hepatic insulin resistanceand sensitivity at the gene expression level has been observedin rodent obese and diabetic models [215 258] Howeverthe mechanism of this coexistence of insulin sensitivity andresistance has not been revealed [261]

Recently the SREBP cleavage-activating protein gene(Scap) an escort protein necessary for generating nuclearforms of SREBPs has been knocked out in insulin-resistantobob mice [262] Deficiency of hepatic Scap reverses liverlipogenesis and steatosis in obobmice However the plasmalevels of glucose and insulin and the hepatic expression levelsof Pck1 andG6pcwere not different between the control obobmice and the obob mice with liver-specific Scap knockout[262] It seems that the suppression of hepatic FA synthesis

12 ISRN Hepatology

is not sufficient to correct insulin resistance Whether otherfactors play a role in the hepatic insulin resistance is still anopen question

The clinical use of RA-based medicine such asisotretinoin (13-cis RA) caused elevation of plasma TGlevels in human subjects [195ndash197] This increase in plasmaTG levels is also observed in rats [201ndash203] From our VAstatus studies we have shown that VA status affected theobesity development in ZF rats and reduced plasma insulinand TG levels in ZL and ZF rats suggesting improvement ofinsulin sensitivity [116] The hepatic expression of Srebp-1cwas reduced in VA-deficient animals [116] RA synergizeswith insulin to induce the expression of Srebp-1c in primaryrat hepatocytes [227] On the other hand RA treatmentinduces Pck1 expression and attenuates insulin-mediatedsuppression of its expression in primary rat hepatocytes [172]All of these observations demonstrate that RA attenuatesinsulin action (insulin-suppressed Pck1 expression) andstill promotes insulin action (insulin-induced Srebp-1cexpression) in the same primary hepatocytes

44 Possible Mechanism by Which RA Production Causes theDevelopment of the Vicious Cycle in Hepatocytes Could RAor other metabolites from VA catabolism be a factor thatcontributes to the hepatic insulin resistance and the viciouscycleUsing the regulation ofPck1 and Srebp-1c as themodel Ihave come upwith the following scheme to show that retinoidmetabolism could be a factor that causes the vicious cycle inthe liver As shown in Figure 3(a) in insulin-sensitive hepa-tocytes RA derived from retinal coordinates with insulin toregulate the expression of Srebp-1c and Pck1 The SREBP-1cprotein is processed to mature form a step that can be facili-tated by insulin [263] The mature form of SREBP-1c entersinto the nucleus and induces the mRNA levels of Raldh1and Fas which are respectively transcribed into RALDH1and FAS RALDH1 catalyzes the conversion of retinal to RAFAS catalyzes the synthesis of palmitate which is esterifiedinto TGs or elongated to longer FAs The Pck1 mRNA isused to translate into PEPCK-C protein which contributesto glucogenogenesis In the insulin-resistant hepatocytes asshown in Figure 3(b) the elevation of Raldh1 expressiondue to leptin deficiency [45] or induction of SREBP-1c byhigh-cholesterol feeding [232] induces the production of RAThe elevated RA levels will stimulate the transcription ofSrebp-1c and Pck1 This leads to more production of SREBP-1c and its mature form in the presence of higher insulinlevels in the insulin-resistant state The induction of SREBP-1c further enhances the transcription of Raldh1 and Fas andtheir corresponding proteins for the production of moreRAs and FAs respectively The RA production and SREBP-1c expression form a feed-forward cycle which causes moreTG and RA production in the insulin-resistant liver At thesame time more of the PEPCK-C protein is generated dueto the elevated Pck1 transcription by RA stimulation whichis not responsive to insulin inhibition as we have shown in[172] This leads to elevated gluconeogenesis in the insulin-resistant liver Eventually the phenotypes appear as if insulin

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1cRetinal

RALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(a) Insulin-sensitive hepatocytes

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1c

RetinalRALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(b) Insulin-resistant hepatocytes

Figure 3 The effects of RA on the insulin-regulated Srebp-1cand Pck1 expression levels the protein levels of SREBP-1c theexpression levels of Raldh1 and Fas and the fatty acid synthesisand gluconeogenesis in insulin-sensitive (a) and insulin-resistant (b)hepatocytes Please see the text in this paper for description Uparrows next to the text indicate induction The intensified weight ofthe lines indicates the induction of that part of the pathway

no longer suppresses gluconeogenesis while it still stimulatesFA synthesis in the insulin-resistant state

5 Perspectives and Future Directions

I have proposed a mechanism by which VA metabolismcontributes to the development of hepatic insulin resistanceIt explains some observations reported in the previous studiesof rodent obese and diabetic models [215 258] However itleavesmore open questionsThefirst one iswhat the initiationfactor is So far the elevated expression of Raldh1 mRNA inthe liver has been observed in ZF rats [45] and mice fed ahigh-cholesterol diet [232] These two conditions cause a lotof physiological changes such as overfeeding in ZF rats andchange of cholesterol biosynthesis in response to the feedingof high-cholesterol diet Knocking down Raldh1 specificallyin hepatocytes is needed to answer these questions The

ISRN Hepatology 13

second question is whether RA synthesis in hepatocytesis a regulated process in response to dietary or hormonalstimulations If Raldh1 is a downstream gene of SREBP-1cit should be regulated when the SREBP-1c level changes Asthe expression of Srebp-1c responds to insulin stimulation andoxysterols the regulation of Raldh1 expression in the livershould be studied The third question is why it is RALDH1but not other RALDHs Specific inhibitors of RALDHsmay be needed to answer this question Last question iswhether we can attenuate insulin resistance by suppressingthe RALDH1 activity in the liver It has been shown thatRaldh1minusminus mice are still insulin sensitive when they are onan HFD [26] This has been attributed to the effects on theadipogenesis However the liver of those knockout mice hasreduced lipid synthesis [231] Further studies are warrantedto answer all of these questions Hopefully it can become anintervention point for the treatment of insulin resistance andmetabolic diseases

Acknowledgments

This work was financially supported by a research grantfrom Allen Foundation Inc (to Guoxun Chen) a start-up fund from the University of Tennessee at Knoxville (toGuoxun Chen) and a Scientist Development Grant fromthe AmericanHeart Association (09SDG2140003 to GuoxunChen) The author thanks his colleague Dr Lauren Gellar forreading through this paper and offering her edits

References

[1] F G Hopkins ldquoFeeding experiments illustrating the impor-tance of accessory factors in normal dietariesrdquo The Journal ofPhysiology vol 44 no 5-6 pp 425ndash460 1912

[2] K J Carpenter ldquoA short history of nutritional science part 3(1912ndash1944)rdquo Journal of Nutrition vol 133 no 10 pp 3023ndash30322003

[3] E V McCollum and M Davis ldquoThe necessity of certain lipinsin the diet during growthrdquo Journal of Biological Chemistry vol15 no 1 pp 167ndash175 1913

[4] T B Osborne and L B Mendel ldquoFeeding experiments with fat-free food mixturesrdquo Journal of Biological Chemistry vol 12 no1 pp 81ndash89 1912

[5] R D Semba ldquoOn the lsquoDiscoveryrsquo of Vitamin Ardquo Annals ofNutrition and Metabolism vol 61 no 3 pp 192ndash198 2012

[6] R Blomhoff and H K Blomhoff ldquoOverview of retinoidmetabolism and functionrdquo Journal of Neurobiology vol 66 no7 pp 606ndash630 2006

[7] A Sommer ldquoVitamin A deficiency and clinical disease anhistorical overviewrdquo Journal of Nutrition vol 138 no 10 pp1835ndash1839 2008

[8] K J Rothman L L Moore M R Singer U-S Nguyen SMannino and A Milunsky ldquoTeratogenicity of high vitamin Aintakerdquo The New England Journal of Medicine vol 333 no 21pp 1369ndash1373 1995

[9] S Bershad A Rubinstein and J R Paterniti Jr ldquoChanges inplasma lipids and lipoproteins during isotretinoin therapy foracnerdquoThe New England Journal of Medicine vol 313 no 16 pp981ndash985 1985

[10] N Rodondi R Darioli A-A Ramelet et al ldquoHigh risk forhyperlipidemia and the metabolic syndrome after an episodeof hypertriglyceridemia during 13-cis retinoic acid therapy foracne a pharmacogenetic studyrdquo Annals of Internal Medicinevol 136 no 8 pp 582ndash589 2002

[11] H-U Klor A Weizel M Augustin et al ldquoThe impact oforal vitamin A derivatives on lipid metabolism what recom-mendations can be derived for dealing with this issue in thedaily dermatological practicerdquo Journal of the German Societyof Dermatology vol 9 no 8 pp 600ndash607 2011

[12] R M Russell ldquoThe vitamin A spectrum from deficiency totoxicityrdquoThe American Journal of Clinical Nutrition vol 71 no4 pp 878ndash884 2000

[13] A C Ross B Caballero R J Cousins K L Tucker and T RZiegler Modern Nutrition in Health and Diseases 11th edition2012

[14] E H Harrison ldquoMechanisms of digestion and absorption ofdietary vitamin Ardquo Annual Review of Nutrition vol 25 no 1pp 87ndash103 2005

[15] M R Lakshman ldquoAlpha and omega of carotenoid cleavagerdquoJournal of Nutrition vol 134 no 1 pp 241ndash245 2004

[16] I Potrykus ldquoNutritionally enhanced rice to combat malnutri-tion disorders of the poorrdquo Nutrition Reviews vol 61 no 6 ppS101ndashS104 2003

[17] A Wyss ldquoCarotene oxygenases a new family of double bondcleavage enzymesrdquo Journal of Nutrition vol 134 no 1 pp 246ndash250 2004

[18] R Kawaguchi J Yu J Honda et al ldquoA membrane receptor forretinol binding protein mediates cellular uptake of vitamin ArdquoScience vol 315 no 5813 pp 820ndash825 2007

[19] P Alapatt F Guo S M Komanetsky et al ldquoLiver retinoltransporter and receptor for serum retinol-binding protein(RBP4)rdquo Journal of Biological Chemistry vol 288 no 2 pp1250ndash1265 2013

[20] A R Moise N Noy K Palczewski and W S Blaner ldquoDeliveryof retinoid-based therapies to target tissuesrdquo Biochemistry vol46 no 15 pp 4449ndash4458 2007

[21] G Duester ldquoFamilies of retinoid dehydrogenases regulatingvitamin A function Production of visual pigment and retinoicacidrdquo European Journal of Biochemistry vol 267 no 14 pp4315ndash4324 2000

[22] M Theodosiou V Laudet and M Schubert ldquoFrom carrotto clinic an overview of the retinoic acid signaling pathwayrdquoCellular andMolecular Life Sciences vol 67 no 9 pp 1423ndash14452010

[23] J L Napoli ldquoInteractions of retinoid binding proteins andenzymes in retinoidmetabolismrdquoBiochimica et BiophysicaActavol 1440 no 2-3 pp 139ndash162 1999

[24] X Chai M H E M Boerman Y Zhai and J L NapolildquoCloning of a cDNA for liver microsomal retinol dehydro-genase A tissue-specific short-chain alcohol dehydrogenaserdquoJournal of Biological Chemistry vol 270 no 8 pp 3900ndash39041995

[25] B X Wu G Moiseyev Y Chen B Rohrer R K Crouch andJ-XMa ldquoIdentification of RDH10 an all-trans retinol dehydro-genase in retinal Muller cellsrdquo Investigative Ophthalmology andVisual Science vol 45 no 11 pp 3857ndash3862 2004

[26] O Ziouzenkova G Orasanu M Sharlach et al ldquoRetinalde-hyde represses adipogenesis and diet-induced obesityrdquo NatureMedicine vol 13 no 6 pp 695ndash702 2007

14 ISRN Hepatology

[27] J L Napoli ldquoPhysiological insights into all-trans-retinoic acidbiosynthesisrdquo Biochimica et Biophysica Acta vol 1821 no 1 pp152ndash167 2012

[28] G Wolf ldquoTissue-specific increases in endogenous all-transretinoic acid possible contributing factor in ethanol toxicityrdquoNutrition Reviews vol 68 no 11 pp 689ndash692 2010

[29] P V Bhat J Labrecque JM Boutin A Lacroix andA YoshidaldquoCloning of a cDNA encoding rat aldehyde dehydrogenase withhigh activity for retinal oxidationrdquoGene vol 166 no 2 pp 303ndash306 1995

[30] M Lin M Zhang M Abraham S M Smith and J LNapoli ldquoMouse retinal dehydrogenase 4 (RALDH4) molecularcloning cellular expression and activity in 9-cis-retinoic acidbiosynthesis in intact cellsrdquo Journal of Biological Chemistry vol278 no 11 pp 9856ndash9861 2003

[31] F A Mic A Molotkov X Fan A E Cuenca and GDuester ldquoRALDH3 a retinaldehyde dehydrogenase that gener-ates retinoic acid is expressed in the ventral retina otic vesicleand olfactory pit during mouse developmentrdquo Mechanisms ofDevelopment vol 97 no 1-2 pp 227ndash230 2000

[32] X Wang P Penzes and J L Napoli ldquoCloning of a cDNAencoding an aldehyde dehydrogenase and its expression inEscherichia coli recognition of retinal as substraterdquo Journal ofBiological Chemistry vol 271 no 27 pp 16288ndash16293 1996

[33] A Molotkov and G Duester ldquoGenetic evidence that retinalde-hyde dehydrogenase Raldh1 (Aldh1a1) functions downstreamof alcohol dehydrogenase Adh1 in metabolism of retinol toretinoic acidrdquo Journal of Biological Chemistry vol 278 no 38pp 36085ndash36090 2003

[34] G Elizondo J Corchero E Sterneck and F J GonzalezldquoFeedback inhibition of the retinaldehyde dehydrogenase geneALDH1 by retinoic acid through retinoic acid receptor 120572and CCAATenhancer-binding protein 120573rdquo Journal of BiologicalChemistry vol 275 no 50 pp 39747ndash39753 2000

[35] G Elizondo I M Medina-Dıaz R Cruz F J Gonzalez and LVega ldquoRetinoic acid modulates retinaldehyde dehydrogenase 1gene expression through the induction of GADD153-CEBP120573interactionrdquo Biochemical Pharmacology vol 77 no 2 pp 248ndash257 2009

[36] K Fujiwara M Kikuchi K Horiguchi et al ldquoEstrogen receptoralpha regulates retinaldehyde dehydrogenase 1 expression in ratanterior pituitary cellsrdquo Endocrine Journal vol 56 no 8 pp963ndash973 2009

[37] K Fujiwara F Maekawa M Kikuchi S Takigami T Yadaand T Yashiro ldquoExpression of retinaldehyde dehydrogenase(RALDH)2 and RALDH3 but not RALDH1 in the developinganterior pituitary glands of ratsrdquo Cell and Tissue Research vol328 no 1 pp 129ndash135 2007

[38] GWolf ldquoThe enzymatic cleavage of 120573-carotene still controver-sialrdquo Nutrition Reviews vol 53 no 5 pp 134ndash137 1995

[39] S Abu-Abed P Dolle D Metzger B Beckett P Chambonand M Petkovich ldquoThe retinoic acid-metabolizing enzymeCYP26A1 is essential for normal hindbrain patterning verte-bral identity and development of posterior structuresrdquo Genesand Development vol 15 no 2 pp 226ndash240 2001

[40] M A Leo S Iida and C S Lieber ldquoRetinoic acid metabolismby a system reconstituted with cytochrome P-450rdquo Archives ofBiochemistry and Biophysics vol 234 no 1 pp 305ndash312 1984

[41] MA Leo JM Lasker J L Raucy C-I KimM Black andC SLieber ldquoMetabolism of retinol and retinoic acid by human livercytochrome P450IIC8rdquoArchives of Biochemistry and Biophysicsvol 269 no 1 pp 305ndash312 1989

[42] R Quere A Baudet B Cassinat et al ldquoPharmacogenomicanalysis of acute promyelocytic leukemia cells highlightsCYP26cytochrome metabolism in differential all-trans retinoic acidsensitivityrdquo Blood vol 109 no 10 pp 4450ndash4460 2007

[43] J AWhite B Beckett-Jones Y-D Guo et al ldquocDNA cloning ofhuman retinoic acid-metabolizing enzyme (hP450RAI) identi-fies a novel family of cytochromes p450 (CYP26)rdquo Journal ofBiological Chemistry vol 272 no 30 pp 18538ndash18541 1997

[44] Y Zhang R Zolfaghari Reza and A C Ross ldquoMultiple retinoicacid response elements cooperate to enhance the inducibility ofCYP26A1 gene expression in liverrdquo Gene vol 464 no 1-2 pp32ndash43 2010

[45] Y Li Y Zhang R Li et al ldquoThe hepatic raldh1 expression iselevated in Zucker fatty rats and its over-expression introducedthe retinal-induced Srebp-1c expression in INS-1 cellsrdquo PLoSONE vol 7 no 9 Article ID e45210 2012

[46] R M Evans ldquoThe nuclear receptor superfamily a Rosetta stonefor physiologyrdquo Molecular Endocrinology vol 19 no 6 pp1429ndash1438 2005

[47] P Chambon ldquoA decade of molecular biology of retinoic acidreceptorsrdquo FASEB Journal vol 10 no 9 pp 940ndash954 1996

[48] D J Mangelsdorf and RM Evans ldquoThe RXR heterodimers andorphan receptorsrdquo Cell vol 83 no 6 pp 841ndash850 1995

[49] J E Balmer and R Blomhoff ldquoA robust characterization ofretinoic acid response elements based on a comparison of sitesin three speciesrdquo Journal of Steroid Biochemistry and MolecularBiology vol 96 no 5 pp 347ndash354 2005

[50] R Kurokawa J DiRenzo M Boehm et al ldquoRegulation ofretinoid signalling by receptor polarity and allosteric control ofligand bindingrdquo Nature vol 371 no 6497 pp 528ndash531 1994

[51] A Cvekl and W-L Wang ldquoRetinoic acid signaling in mam-malian eye developmentrdquo Experimental Eye Research vol 89no 3 pp 280ndash291 2009

[52] V Dupe M Davenne J Brocard et al ldquoIn vivo functional anal-ysis of the Hoxa-1 31015840 retinoic acid response element (31015840RARE)rdquoDevelopment vol 124 no 2 pp 399ndash410 1997

[53] A C Ross ldquoRetinoid production and catabolism role of dietin regulating retinol esterification and retinoic acid oxidationrdquoJournal of Nutrition vol 133 no 1 pp 291ndash296 2003

[54] T Moore and P D Holmes ldquoThe production of experimentalvitamin A deficiency in rats andmicerdquo Laboratory Animals vol5 no 2 pp 239ndash250 1971

[55] A C Ross and E H Harrison ldquoVitamin A and carotenoidsrdquoin Handbook of Vitamins D E McCormick R R Rucker J WSuttie et al Eds CRC Press Boca Raton Fla USA 4th edition2006

[56] A Chawta J J Repa R M Evans and D J MangelsdorfldquoNuclear receptors and lipid physiology opening the x-filesrdquoScience vol 294 no 5548 pp 1866ndash1870 2001

[57] C K Glass and M G Rosenfeld ldquoThe coregulator exchangein transcriptional functions of nuclear receptorsrdquo Genes andDevelopment vol 14 no 2 pp 121ndash141 2000

[58] A L Bookout Y Jeong M Downes R T Yu R M EvansandD JMangelsdorf ldquoAnatomical profiling of nuclear receptorexpression reveals a hierarchical transcriptional networkrdquo Cellvol 126 no 4 pp 789ndash799 2006

[59] B Mascrez M Mark W Krezel et al ldquoDifferential contribu-tions of AF-1 andAF-2 activities to the developmental functionsof RXR120572rdquo Development vol 128 no 11 pp 2049ndash2062 2001

[60] D Li T Li F Wang H Tian and H H Samuels ldquoFunctionalevidence for retinoid X receptor (RXR) as a nonsilent partner

ISRN Hepatology 15

in the thyroid hormone receptorRXR heterodimerrdquoMolecularand Cellular Biology vol 22 no 16 pp 5782ndash5792 2002

[61] F M Sladek W Zhong E Lai and J E Darnell Jr ldquoLiver-enriched transcription factor HNF-4 is a novel member ofthe steroid hormone receptor superfamilyrdquo Genes and Develop-ment vol 4 no 12 pp 2353ndash2365 1990

[62] K Yamagata H Furuta N Oda et al ldquoMutations in thehepatocyte nuclear factor-4120572 gene inmaturity-onset diabetes ofthe young (MODY1)rdquo Nature vol 384 no 6608 pp 458ndash4601996

[63] M Stoffel and S ADuncan ldquoThematurity-onset diabetes of theyoung (MODY1) transcription factor HNF4120572 regulates expres-sion of genes required for glucose transport and metabolismrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 24 pp 13209ndash13214 1997

[64] M Lehto P-O Bitzen B Isomaa et al ldquoMutation in the HNF-4120572 gene affects insulin secretion and triglyceride metabolismrdquoDiabetes vol 48 no 2 pp 423ndash425 1999

[65] G P Hayhurst Y-H Lee G Lambert J M Ward and F JGonzalez ldquoHepatocyte nuclear factor 4120572 (Nuclear receptor 2A1)is essential formaintenance of hepatic gene expression and lipidhomeostasisrdquo Molecular and Cellular Biology vol 21 no 4 pp1393ndash1403 2001

[66] U Roth K Jungermann and T Kietzmann ldquoActivation ofglucokinase gene expression by hepatic nuclear factor 4120572 inprimary hepatocytesrdquo Biochemical Journal vol 365 no 1 pp223ndash228 2002

[67] S Mandard R Stienstra P Escher et al ldquoGlycogen synthase2 is a novel target gene of peroxisome proliferator-activatedreceptorsrdquo Cellular and Molecular Life Sciences vol 64 no 9pp 1145ndash1157 2007

[68] F Rajas A Gautier I Bady S Montano and G MithieuxldquoPolyunsaturated fatty acyl coenzyme a suppress the glucose-6-phosphatase promoter activity bymodulating the DNA bindingof hepatocyte nuclear factor 4120572rdquo Journal of Biological Chemistryvol 277 no 18 pp 15736ndash15744 2002

[69] B Viollet A Kahn and M Raymondjean ldquoProtein kinase A-dependent phosphorylation modulates DNA-binding activityof hepatocyte nuclear factor 4rdquoMolecular and Cellular Biologyvol 17 no 8 pp 4208ndash4219 1997

[70] L Palanker J M Tennessen G Lam and C S Thum-mel ldquoDrosophila HNF4 regulates lipid mobilization and 120573-oxidationrdquo Cell Metabolism vol 9 no 3 pp 228ndash239 2009

[71] A Miura K Yamagata M Kakei et al ldquoHepatocyte nuclearfactor-4120572 is essential for glucose-stimulated insulin secretion bypancreatic 120573-cellsrdquo Journal of Biological Chemistry vol 281 no8 pp 5246ndash5257 2006

[72] R Bartoov-Shifman R Hertz H Wang C B Wollheim JBar-Tana and M D Walker ldquoActivation of the insulin genepromoter through a direct effect of hepatocyte nuclear factor4120572rdquo Journal of Biological Chemistry vol 277 no 29 pp 25914ndash25919 2002

[73] H Wang P Maechler P A Antinozzi K A Hagenfeldt andC B Wollheim ldquoHepatocyte nuclear factor 4120572 regulates theexpression of pancreatic 120573-cell genes implicated in glucosemetabolism and nutrient-induced insulin secretionrdquo Journal ofBiological Chemistry vol 275 no 46 pp 35953ndash35959 2000

[74] K Reue T Leff and J L Breslow ldquoHuman apolipoproteinCIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factorsrdquo Journal ofBiological Chemistry vol 263 no 14 pp 6857ndash6864 1988

[75] T Leff K Reue A Melian H Culver and J L BreslowldquoA regulatory element in the apoCIII promoter that directshepatic specific transcription binds to proteins in expressingand nonexpressing cell typesrdquo Journal of Biological Chemistryvol 264 no 27 pp 16132ndash16137 1989

[76] S N Lavrentiadou M Hadzopoulou-Cladaras D Kardassisand V I Zannis ldquoBinding specificity and modulation of thehuman apocIII promoter activity by heterodimers of ligand-dependent nuclear receptorsrdquo Biochemistry vol 38 no 3 pp964ndash975 1999

[77] T R Magee Y Cai M E El-Houseini J Locker and Y-JY Wan ldquoRetinoic acid mediates down-regulation of the 120572-fetoprotein gene through decreased expression of hepatocytenuclear factorsrdquo Journal of Biological Chemistry vol 273 no 45pp 30024ndash30032 1998

[78] A Qian Y Cai T R Magee and Y J Y Wan ldquoIdentificationof retinoic acid-responsive elements on the HNF1alpha andHNF4alpha genesrdquo Biochemical and Biophysical Research Com-munications vol 276 no 3 pp 837ndash842 2000

[79] H Nakshatri and P Chambon ldquoThe directly repeatedRG(GT)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites forRAR RXR HNF-4 and ARP-1 homo- and heterodimersrdquoJournal of Biological Chemistry vol 269 no 2 pp 890ndash9021994

[80] T Makita G Hernandez-Hoyos T H-P Chen H Wu E VRothenberg and H M Sucov ldquoA developmental transition indefinitive erythropoiesis erythropoietin expression is sequen-tially regulated by retinoic acid receptors andHNF4rdquoGenes andDevelopment vol 15 no 7 pp 889ndash901 2001

[81] T I Kambe J Tada-Kambe Y Kuge Y Yamaguchi-Iwai MNagao and R Sasaki ldquoRetinoic acid stimulates erythropoietingene transcription in embryonal carcinoma cells through thedirect repeat of a steroidthyroid hormone receptor responseelement half-site in the hypoxia-response enhancerrdquo Blood vol96 no 9 pp 3265ndash3271 2000

[82] F-J Lin J Qin K Tang S Y Tsai and M-J Tsai ldquoCoup drsquoEtatan orphan takes controlrdquo Endocrine Reviews vol 32 no 3 pp404ndash421 2011

[83] L-H Wang S Y Tsai R G Cook W G Beattie M-J Tsaiand BW OrsquoMalley ldquoCOUP transcription factor is a member ofthe steroid receptor superfamilyrdquoNature vol 340 no 6229 pp163ndash166 1989

[84] X Leng A J Cooney S Y Tsai and M-J Tsai ldquoMolecularmechanisms of COUP-TF-mediated transcriptional repressionevidence for transrepression and active repressionrdquo Molecularand Cellular Biology vol 16 no 5 pp 2332ndash2340 1996

[85] L Li X Xie J Qin et al ldquoThe nuclear orphan receptorCOUP-TFII plays an essential role in adipogenesis glucosehomeostasis and energy metabolismrdquo Cell Metabolism vol 9no 1 pp 77ndash87 2009

[86] F A Pereira Q Yuhong G Zhou M-J Tsai and S YTsai ldquoThe orphan nuclear receptor COUP-TFII is required forangiogenesis and heart developmentrdquo Genes and Developmentvol 13 no 8 pp 1037ndash1049 1999

[87] N Takamoto I Kurihara K Lee F J DeMayo M-J Tsai andS Y Tsai ldquoHaploinsufficiency of chicken ovalbumin upstreampromoter transcription factor II in female reproductionrdquoMolec-ular Endocrinology vol 19 no 9 pp 2299ndash2308 2005

[88] P Zhang M Bennoun C Gogard et al ldquoExpression of COUP-TFII in metabolic tissues during developmentrdquo Mechanisms ofDevelopment vol 119 no 1 pp 109ndash114 2002

16 ISRN Hepatology

[89] Z Xu S Yu C-H Hsu J Eguchi and E D Rosen ldquoTheorphan nuclear receptor chicken ovalbumin upstream pro-moter-transcription factor II is a critical regulator of adipogene-sisrdquoProceedings of theNationalAcademy of Sciences of theUnitedStates of America vol 105 no 7 pp 2421ndash2426 2008

[90] P Bardoux P Zhang D Flamez et al ldquoEssential role of chickenovalbumin upstreampromoter-transcription factor II in insulinsecretion and insulin sensitivity revealed by conditional geneknockoutrdquo Diabetes vol 54 no 5 pp 1357ndash1363 2005

[91] G Achatz B Holzl R Speckmayer C Hauser F Sandhoferand B Paulweber ldquoFunctional domains of the human orphanreceptor ARP-1COUP-TFII involved in active repression andtransrepressionrdquo Molecular and Cellular Biology vol 17 no 9pp 4914ndash4932 1997

[92] S A Kliewer K Umesono R A Heyman D J MangelsdorfJ A Dyck and R M Evans ldquoRetinoid X receptor-COUP-TFinteractionsmodulate retinoic acid signalingrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol89 no 4 pp 1448ndash1452 1992

[93] A J Cooney S Y Tsai BW OrsquoMalley andM-J Tsai ldquoChickenovalbumin upstreampromoter transcription factor (COUP-TF)dimers bind to different GGTCA response elements allowingCOUP-TF to repress hormonal induction of the vitamin D3thyroid hormone and retinoic acid receptorsrdquo Molecular andCellular Biology vol 12 no 9 pp 4153ndash4163 1992

[94] SW Kruse K Suino-Powell X E Zhou et al ldquoIdentification ofCOUP-TFII orphannuclear receptor as a retinoic acid-activatedreceptorrdquo PLoS Biology vol 6 no 9 Article ID e227 2008

[95] J P Berger T E Akiyama and P T Meinke ldquoPPARs thera-peutic targets for metabolic diseaserdquo Trends in PharmacologicalSciences vol 26 no 5 pp 244ndash251 2005

[96] JM Peters andF J Gonzalez ldquoSorting out the functional role(s)of peroxisome proliferator-activated receptor-120573120575 (PPAR120573120575)in cell proliferation and cancerrdquo Biochimica et Biophysica Actavol 1796 no 2 pp 230ndash241 2009

[97] A Tenenbaum and E Fisman ldquoBalanced pan-PPAR activatorbezafibrate in combination with statin comprehensive lipidscontrol and diabetes preventionrdquo Cardiovascular Diabetologyvol 11 no 1 article 140 2012

[98] O Braissant F Foufelle C Scotto M Dauca and W WahlildquoDifferential expression of peroxisome proliferator-activatedreceptors (PPARs) tissue distribution of PPAR-120572 -120573 and -120574 inthe adult ratrdquo Endocrinology vol 137 no 1 pp 354ndash366 1996

[99] H Higashiyama A N Billin Y Okamoto M Kinoshita andS Asano ldquoExpression profiling of Peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues usingtissue microarrayrdquo Histochemistry and Cell Biology vol 127 no5 pp 485ndash494 2007

[100] P S Jones R Savory P Barratt et al ldquoChromosomal local-isation inducibility tissue-specific expression and strain dif-ferences in three murine peroxisome-proliferator-activated-receptor genesrdquo European Journal of Biochemistry vol 233 no1 pp 219ndash226 1995

[101] S A Kliewer B M Forman B Blumberg et al ldquoDifferentialexpression and activation of a family of murine peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no15 pp 7355ndash7359 1994

[102] E E Girroir H E Hollingshead P He B Zhu G H Perdewand J M Peters ldquoQuantitative expression patterns of peroxi-some proliferator-activated receptor-120573120575 (PPAR120573120575) protein in

micerdquo Biochemical and Biophysical Research Communicationsvol 371 no 3 pp 456ndash461 2008

[103] P Escher O Braissant S Basu-Modak L Michalik W Wahliand B Desvergne ldquoRat PPARs quantitative analysis in adult rattissues and regulation in fasting and refeedingrdquo Endocrinologyvol 142 no 10 pp 4195ndash4202 2001

[104] D Auboeuf J Rieusset L Fajas et al ldquoTissue distributionand quantification of the expression of mRNAs of peroxi-some proliferator-activated receptors and liver X receptor-120572 inhumans no alteration in adipose tissue of obese and NIDDMpatientsrdquo Diabetes vol 46 no 8 pp 1319ndash1327 1997

[105] N ShawM Elholm andN Noy ldquoRetinoic acid is a high affinityselective ligand for the peroxisome proliferator-activated recep-tor 120573120575rdquo Journal of Biological Chemistry vol 278 no 43 pp41589ndash41592 2003

[106] G Wolf ldquoRetinoic acid as cause of cell proliferation or cellgrowth inhibition depending on activation of one of twodifferent nuclear receptorsrdquoNutrition Reviews vol 66 no 1 pp55ndash59 2008

[107] T T Schug D C Berry N S Shaw S N Travis and N NoyldquoOpposing effects of retinoic acid on cell growth result fromalternate activation of two different nuclear receptorsrdquo Cell vol129 no 4 pp 723ndash733 2007

[108] D C Berry and N Noy ldquoAll-trans-retinoic acid repressesobesity and insulin resistance by activating both peroxisomeproliferation-activated receptor 120573120575 and retinoic acid receptorrdquoMolecular and Cellular Biology vol 29 no 12 pp 3286ndash32962009

[109] D C Berry D DeSantis H Soltanian C M Croniger andN Noy ldquoRetinoic acid upregulates preadipocyte genes to blockadipogenesis and suppress diet-induced obesityrdquo Diabetes vol61 no 5 pp 1112ndash1121 2012

[110] M G Borland C Khozoie P P Albrecht et al ldquoStableover-expression of PPAR120573120575 and PPAR120574 to examine receptorsignaling in human HaCaT keratinocytesrdquo Cellular Signallingvol 23 no 12 pp 2039ndash2050 2011

[111] S E OrsquoSullivan and D A Kendall ldquoCannabinoid activationof peroxisome proliferator-activated receptors potential formodulation of inflammatory diseaserdquo Immunobiology vol 215no 8 pp 611ndash616 2010

[112] Z C Yan D Y Liu L L Zhang et al ldquoExercise reduces adiposetissue via cannabinoid receptor type 1 which is regulated byperoxisome proliferator-activated receptor-120575rdquo Biochemical andBiophysical Research Communications vol 354 no 2 pp 427ndash433 2007

[113] J D McGarry ldquoWhat if Minkowski had been ageusic Analternative angle on diabetesrdquo Science vol 258 no 5083 pp766ndash770 1992

[114] TMoore ldquoVitaminA and carotene the vitaminA reserve of theadult human being in health and diseaserdquo Biochemical Journalvol 31 no 1 pp 155ndash164 1937

[115] GWolfMD Lane and B C Johnson ldquoStudies on the functionof vitamin A in metabolismrdquo Journal of Biological Chemistryvol 225 no 2 pp 995ndash1008 1957

[116] Y Zhang R Li Y Li W Chen S Zhao and G Chen ldquoVitaminA status affects obesity development and hepatic expression ofkey genes for fuel metabolism in Zucker fatty ratsrdquoBiochemistryand Cell Biology vol 90 no 4 pp 548ndash557 2012

[117] M Singh V N Singh and T A Venkitasubramanian ldquoEarlyeffects of feeding excess vitamin A hepatic glycogen bloodlactic acid plasma nefa and glucose tolerance in ratsrdquo LifeSciences vol 7 no 5 pp 239ndash247 1968

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

8 ISRN Hepatology

Hepatocyte

Induction

Induction

Induction

1 2

Gck

Pck1

Cell membraneCytosol

RA RA

RARESynergy

Signalcascade Insulin

AttenuationNuclear

membrane NucleusRAREs

Inhibitio

n

Figure 2 RA synergizes with insulin to induce Gck expressionand attenuates insulin-suppressed Pck1 expression RA inducesthe expression levels of Gck and Pck1 via the activation of bothRARRXR (the oval dimmers on the RAREs) in the absenceof insulin Insulin alone stimulates the expression of Gck andsuppresses the expression of Pck1 In the presence of both insulinand RA the expression of Gck is further increased (synergy) Onthe other hand the insulin-mediated suppression of Pck1 expressionis attenuated This is because RA still induces Pck1 expressionvia activation of RAR in the presence of insulin Therefore Pck1transcript level in the RA + insulin group is higher than that in theinsulin group (attenuation)

in VA-deficient state [116] VA deficiency only reduces thehepatic Pck1mRNA in the Zucker fatty (ZF) rats [116]

It is important to note that the respective activities of GKand PEPCK-C are induced in different physiological condi-tions For example insulin induces Gck and suppresses Pck1expression as shown in Figure 2 In primary rat hepatocytesactivation of either RARs or RXRs by RA is sufficient toinduce the expression of both Pck1 [172] and Gck [137] How-ever activation of RAR potentiates (for the insulin-mediatedinduction of Gck expression) and attenuates (for the insulin-mediated suppression of Pck1 expression) insulin actionsat the same time in the same hepatocytes For Gck RA-mediated activation of RARs and RXRs can be potentiated byinsulin [137] which results in the synergy For Pck1 only RA-activated RXRs but not RARs are inhibited by insulin whichresults in the attenuation [172] This causes the production ofmore Pck1 mRNA in the presence of RA than in the absenceof it even in the insulin-suppressed state It indicates that themechanisms of RA-mediated activation of RARs and RXRsprobably depend on the promoter context or the isoformsassociated with the promoters of their downstream genesin the presence of insulin Therefore the roles of retinoidsin hepatic glucose metabolism deserve further investigationespecially the roles of the interactions between retinoidsand insulin signaling pathways in the regulation of genetranscription

24 Role of RBP4 in Insulin Resistance Plasma VA is boundto RBP4 which is mainly produced in the liver [13] TheRbp4 mRNA is also expressed to a certain extent in adipose

tissues and kidney [13] In the plasma retinol-RBP4 complexis associated with transthyretin (TTR) a process to increasethe size of the holo-RBP4-TTR complex to reduce the lossduring renal filtration [173]

Recently the plasma RBP4 has been suggested to playroles in metabolic homeostasis It has been reported thatinsulin-resistant human subjects and animals have higherplasma RBP4 levels than normal ones due to its elevatedproduction from adipose tissues [174] In mice RBP4administration has been shown to reduce insulin sensitivityand increase the expression levels of hepatic gluconeogenicgenes such as Pck1 and the catalytic subunit of glucose 6-phosphatase (G6pc) [175] Additionally reduction of plasmaretinol and RBP levels has been reported in type 1 diabeticpatients [176] and in streptozotocin- (STZ-) induced diabeticrats [177] Rbp4 knockout mice have improved insulin sen-sitivity [175] The treatment fenretinide a synthetic retinoidderivative that disrupts the association of RBP4 and TTRimproves insulin sensitivity in HFD-induced obese mice[175]

When a compound specifically developed to disrupt theRBP4 and TTR interaction was used to treat mice it suc-cessfully disrupted the formation of RBP4-TTR complex andcaused the reduction of plasma RBP4 level [178] Howeverthe reduction of plasma RBP4 level did not result in animprovement of insulin sensitivity [178] In addition theimprovement of insulin sensitivity in Rbp4 knockout micecould not be observed in this study [178] Therefore the ele-vation of insulin sensitivity in mice treated with fenretinideis probably due to a mechanism other than the disruption ofRBP-TTR complex and reduction of plasma RBP4 levels

3 Roles of VA in FA and TG Metabolism

FAs are needed for many aspects of cellular functions fromsignal transduction to energy production The continuoussurvival of a given cell depends on the constant energysupplies from the environment or storage sources Thestorage of FA in the form of TG ensures the constant energysupply in a cell or organism for a prolonged period oftime when environment energy is limited In animals thehomeostasis of FA and TG is dynamically regulated by theliver and the adipose tissues in response to nutritional andhormonal stimuli [179 180] During fasting or starvation FAsare released from adipose depots after lipolysis and oxidizedin the liver and muscle for energy production [181] Afterrefeeding dietary and newly synthesized FAs are convertedto TGs for the storage in the adipose tissues [182] On theother hand the altered regulation of this system may causeproblems For example the excessive synthesis and storage ofFAs in the form of TGs can cause the development of obesityand other metabolic diseases

31 The Effects of VA Status on the Body Fat and Plasma LipidProfile VA was first recognized as a dietary lipophilic factorwhich was essential to support the normal growth of labanimals [3 4] Subsequently it was observed that along withthe reduction of body mass the VAD rats that had been fed

ISRN Hepatology 9

aVADdiet at weaning (21 days old) formore than 9weeks hadreduction of carcass fat but not cholesterol content [183] Onthe other hand this reduction of body fat was not observedin the rats of the pair-feeding group which were given thesame amount of a VAS diet in weight and calories as theone consumed by the VAD rats [183] These results indicatethat the reduction of food intake alone could not be used toexplain the depletion of body fat in the VAD rats

The VA status also seems to affect the hepatic expressionof apo AI mRNA The expression of hepatic apo AI hasbeen shown to be sensitive to VA status [184] When theLewis strain rats develop VA deficiency the expression levelof hepatic but not intestinal apo AI mRNA is elevated Thisinduction is dropped upon single dosage of RA treatment[184] On the other hand in the intestine and liver of VA-deficient Wistar rats both all-trans RA and 9-cis RA caninduce apo AI mRNA levels [185] The same treatment canonly induce the mRNA level of apo CIII in the intestine butnot in the liver [185] In humans the plasma VA levels arepositively correlated with the elevations of proteins of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiapatients [186]

When male Wistar rats were fed a VAD diet for 3 monthsafter weaning (21 days old) they had lower plasma TGs andcholesterol levels than the control ones fed a VAS diet [187]When the hepatic synthesis of FAs and phospholipids wasanalyzed in the liver slices the incorporations of [14C]cholineinto phosphatidylcholine and [14C]acetate into FAs were alsoreduced in the VAD rats compared with their VAS controls[187] The VAD rats had lower activities and mRNA levels ofacetyl-CoA carboxylase but higher activity and mRNA levelof carnitine palmitoyltransferase-I than VAS rats had [187]These results demonstrate that there is a reduction of hepaticfatty acid synthesis along with an induction of hepatic fattyacid oxidation in the liver of VAD rats

My lab has conducted experiments and shown that VAstatus affects the obesity development in ZF rats and controlsplasma TG levels in ZL and ZF rats [116] ZF rats a ratmodel of obesity development [188] develop obesity dueto a missense mutation in the extracellular domain of allleptin receptor isoforms [189ndash191] They have been used forthe studies of obesity insulin resistance and other aspectsof metabolic diseases [192 193] We have analyzed growthplasma parameters and expression levels of hepatic genes ofmale ZL and ZF rats fed a VAD or a VAS diet at weaning(21 days of age) for 8 weeks Body masses of ZL and ZF ratsfed the VAD diet are lower than those of their correspondingcontrols fed the VAS diet at the end of the feeding periodThe VAD ZL or ZF rats begin to take less food than the VASones after five weeks on the diet The VAD ZL or ZF rats havelower plasma glucose TG insulin and leptin levels than theircorresponding VAS rats have The liver glycogen content netweights of epididymal fat and liver and fat-to-body massratio (ZL only) in the VAD rats are also lower than those inthe VAS ones [116] This demonstrates that VA status affectsplasma TG levels in both ZF and ZL rats and the obesitydevelopment in ZF rats This phenomenon may be caused by

the combination of VA deficiency and hypoinsulinemia sinceinsulin secretion is impaired in the VAD rats [194]

32 The Development of Hypertriglyceridemia inPatients Receiving Retinoic Acid-Based Treatments

321 The Uses of RA-Based Medicines in Clinic RA-basedmedicines tretinoin (all-trans RA) isotretinoin (13-cis RA)and alitretinoin (9-cis RA) have been used in clinic to treatdiseases such as acute promyelocytic leukemia and skindisorders [11] In fact isotretinoin has been widely used totreat severe acne Early clinical observations indicate that themedical use of isotretinoin in human subjects results in theelevation of their plasma TG levels [195ndash197] A significantportion of patients with acne receiving isotretinoin treatmentdeveloped hypertriglyceridemia [9 10] In addition thesystemic administration of isotretinoin in patients with acneresulted in the elevation of plasma levels of alanine amino-transferase (ALT) and aspartate aminotransferase (AST)indicating the liver damage [198]The hypertriglyceridemia isalso associated with reduced insulin sensitivity and elevatedTG in the very-low-density lipoprotein (VLDL) fraction[195] The treatment of all-trans RA resulted in body massgain and hypertriglyceridemia in patients with acute promye-locytic leukemia [199 200] Moreover RA treatment alsoraises plasma TG levels in rats [201ndash203]

322 The Mechanism of RA-Mediated Hypertriglyceridemiain Patients Apo CIII is produced from liver and consideredan inhibitor of LPL activity [204] Mice with Apoc3 geneknockout have hypotriglyceridemia and enhanced in vivoVLDL-TG clearance [205] On the other hand transgenicmice with overexpression of apo CIII develop hypertriglyc-eridemia [206] The RA-induced hypertriglyceridemia hasbeen attributed to RA-induced apo CIII expression

In healthy human subjects isotretinoin treatment causesa rise of plasma apo CIII protein level [207]This is caused bythe induction of Apoc3 mRNA via the activation of RXR ata RARE in its promoter [207] The plasma TG levels in ratstreated with RXR-specific agonist (LG100268) are inducedrapidly and constantly [208] This results in the reducedactivity of LPL in the heart and skeletal muscle of thoseanimals [208] The RARE is identified in the C3P regionwhich controls the hepatic specific expression of Apoc3 gene[75] Interestingly the same site is also considered to beresponsible for mediating the effects of HNF4120572 and COUP-TFII onApoc3 gene expression [209]The expression ofApoc3seems to be regulated differently by the C3P-binding proteins[75]

It is worth to note that insulin suppresses Apoc3 mRNAexpression in STZ-induced diabetic mice [210] In additionthe activation of RXR by LG100268 treatment induces insulinsensitivity and reduces TG levels in obese and diabetic mice[211] The understanding of the regulatory mechanism thatintegrates hormonal and nutritional signals at the regulatorysites such as C3P in Apoc3 promoter will shed some lightson the regulation of hepatic lipid homeostasis It will also

10 ISRN Hepatology

provide a novel target for the treatment of the RA-inducedhypertriglyeridemia

323 The Effects of RA Treatment on Obesity Developmentin Mice Interestingly the RA administration in rodentscauses reduction of body mass as summarized in [212] Thiskind of reduction of body mass has been associated withenhancement of insulin sensitivity in genetic [213] or DIOmice [108] The mechanisms of RA-mediated attenuation ofinsulin resistance have been thought to be the induction ofenergy expenditure through PPAR120573120575 activation [108] andthe inhibition of adipogenesis throughRXR120574 activation [109]On the other hand retinol can be metabolized in adipose tis-sues [214]Themice with deletion ofRaldh1 gene (Raldh1minusminus)have elevated retinal in their adipose tissues and are resistantto diet-induced obesity and insulin resistance [26] This hasbeen attributed to the suppression of adipogenesis by retinal-inhibited activation of PPAR120574 and RXR [26] It is interestingto note that either retinal or RA can inhibit the adipogenesisand cause the improvement of insulin sensitivity in micebased on these studies

33 Roles of VA and Retinoids in the Regulation of HepaticLipogenic Gene Expression Insulin resistance diabetes andother metabolic abnormalities are associated with profoundchanges of hepatic lipid and glucose metabolismThis can beattributed at least in part to the altered expression of genesinvolved in glucose and lipid metabolism [215] The hepaticlipogenesis contributes to the homeostasis of FAs and TGs

331 The Regulation of Hepatic Srebp-1c Expression by VAStatus and Retinoids Treatment Insulin plays an essentialrole in the hepatic FA synthesis It has been known for a whilethat insulin is needed for the glucose usage for lipogenesis andCO2production in the liver [216] The hepatic FA synthesis

rises sharply and continuously after rats are fasted and thenrefed a high-carbohydrate diet [217] The amount of fattyacid synthase (FAS) is induced in normal rats refed a high-carbohydrate diet after fasting and in STZ-induced diabeticrats after insulin administration [218] In the insulin-deficientrats the induction of FAS after refeeding occurs only wheninsulin injection is injected [219] a process attributed to theinduction of FAS gene (Fas) [220 221]

The transcription of hepatic Fas is controlled by a tran-scription factor named SREBP-1c [222] In the liver-specificSrebp-1c knockoutmouse liver the induction of Fas and otherlipogenic genes by refeeding after fasting is blunted [223]Interestingly insulin also specifically induces the Srebp-1cexpression in the liver [224] via two liver X receptor elements(LXREs) and one sterol-responsive element (SRE) [225]However in liver-specific insulin receptor knockoutmice theinduction of hepatic Srebp-1c by refeeding largely remainedunchanged [226] This suggests that nutrient-derived signalsmay activate downstream of insulin receptor signaling path-way to regulate Srebp-1c expression and hepatic lipogenesis[226]

As stated in the previous section my research group hasobserved that the VAD ZL and ZF rats have lower plasma TG

levels than their VAS controls [116] This is accompanied bythe reduction of the hepatic expression of Srebp-1cmRNA inVA-deficient animals [116] My research group has reportedfor the first time that retinoids synergize with insulin toinduce the expression of Srebp-1c in primary rat hepatocytes[227] Further analysis of the Srebp-1c promoter reveals thatthe previous identified LXREs responsible for mediatinginsulin-induced Srebp-1c expression are also RAREs [227]These observations show that retinoids (nutritional) andinsulin (hormonal) signals converge to regulate the FAsynthesis in the liver

332 The Effects of VA Catabolism on the Regulation of Srebp-1c Expression in Primary Rat Hepatocytes More recentlyretinoids have been proposed to play roles in glucose and lipidmetabolism and to maintain energy homeostasis [228 229]VA (retinol) is reversibly converted into retinal and retinalis irreversibly converted into RA [23] Retinal the precursorof RA production is able to synergize with insulin to inducethe Srebp-1c expression in primary rat hepatocytes [227]This suggests that the dynamic production of RA influencesthe expression of hepatic lipogenic genes It has led us toinvestigate the roles of RA production in the insulin-resistantanimals

In the liver of the Raldh1minusminus mice RA production isreduced in response to a load of retinol [230] The Raldh1minusminusmice are resistant to the development of obesity and insulinresistance after being fed an HFD [26] This is attributed tothe elevation of retinal content due to the lack of conversionof retinal to RA in the adipose tissues of the Raldh1minusminusmice Additionally the liver of the Raldh1minusminus mice hasaltered regulation of the genes for gluconeogenesis andsignificantly attenuated hepatic TG synthesis indicating theimportant role of hepatic VAmetabolism in glucose and lipidhomeostasis [231]

The hepatic expression levels of RALDH1 and RALDH2are induced in mice fed a high-cholesterol diet [232] SREsare located in the promoters of these two genes whichare induced by SREBP-1c overexpression The expression ofSrebp-1c is induced by the oxysterols derived from the high-cholesterol diet [232] This research work demonstrates theinteraction of cholesterol and RA metabolism in the liver Inaddition it has been shown that the level of Raldh1mRNA iselevated in the kidney of dbdb mice [233] Both dbdb miceand ZF rats develop obesity due to the mutation of leptinreceptor [234]

In an attempt to understand the roles of VA metabolismin the states of metabolic diseases we have compared theexpression levels of enzymes responsible for the productionof retinal and RA in the freshly isolated and cultured primaryhepatocytes from ZL rats and ZF rats [45] We have foundthat in the primary rat hepatocytes the enzymes responsiblefor the conversions of retinol to retinal and from retinal toRA are most likely RDH2 and RALDH1 respectively Theexpression levels of Raldh1 mRNA and its protein are higherin hepatocytes from ZF rats than in those from ZL rats[45] When overexpressed RALDH1 introduces the retinal-mediated induction of Srebp-1c in INS-1 cells which do not

ISRN Hepatology 11

respond to retinal in our previous study [227] These resultsindicate that insulin-resistant animals such as ZF rats mayhave alterations in retinoids metabolism

Thus we have hypothesized that the change of RAproduction from the oversupply of dietary VA due to thehyperphagia of ZF rats results in higher Srebp-1c expressionin ZF hepatocytes [45] The elevated SREBP-1c expressioncan further induceRaldh1 expression to create a feed-forwardmechanism that could be one of the reasons responsible forthe increased lipogenesis in the liver of ZF rats All of theseobservations indicate the potential roles of RA metabolismin the development of obesity and insulin resistance whichdeserves to be further studied

4 VArsquos Roles in Mediating Hepatic InsulinAction and Insulin Resistance

41 Insulin and Its Signal Transduction The insulin moleculeis made of two chains linked by one intra- and one interchaindisulfide bonds [235] The insulin receptor is a transmem-brane and heterotetramer tyrosine kinase receptor (two 120572and two 120573 subunits) linked by disulfide bonds as well [236]The binding of insulin to its receptor causes conformationchanges and transphosphorylation of the 120573-subunit tyrosinekinase [237 238] which initiates the signal transduction[239] Protein-protein interactions are involved in the trans-duction of insulin signalThe signal is transduced bymultiplecomponents in a complex network containing cascades ofkinases and phosphatases [240 241] The first intracellularcomponents mediating insulin signals are insulin recep-tor substrates (IRSs) protein molecules phosphorylated byinsulin receptor 120573-subunit and mediating insulin signals[242]

The insulin signal event is further amplified byphosphatidylinositide 3-kinases (PI3K)protein kinaseB (PKBAkt) pathway and GRB2mitogen-activated proteinkinase (MAPK) pathway [243ndash245] Another serinethre-onine kinase that can be activated by PI3K is the atypicalprotein kinase C [246] Human liver expresses severalprotein-tyrosine phosphatases (PTPs) [247] Okadai acid aninhibitor of protein phosphatase type 2A and type 1 inhibitsglycogen synthesis and insulin-stimulated Gck expression inprimary rat hepatocytes indicating that dephosphorylationmechanism may also participate in mediating insulinsignaling [248] These components are shared by insulin-likegrowth factor (IGF) receptor and involved in mediatinginsulin and IGF signals [249]

42 Metabolic Diseases and Insulin Resistance The rise ofthe number of people with one or more metabolic diseasessuch as obesity and diabetes in the world has become apublic health problem [250] The interactions of genetic andenvironmentalnutritional factors may be responsible for thecurrent rise of metabolic diseases The long evolutionaryprocess has equipped human and animal bodieswith a varietyof regulatory mechanisms controlling these interactions [251252] Human diets contain not only energy derived frommacronutrients but also micronutrients and other factors

which may influence the metabolic outcomes The roles ofindividual micronutrients in the development of metabolicdiseases are still unrevealed

One common property of human obesity and NIDDMis insulin resistance in which a given amount of insulinproduces less than normal physiological responses Dietaryfactors and manipulations have been considered to play arole in the development of insulin resistance in humans andanimals For example feeding an HFD to young and insulin-sensitive subjects for two days causes the development ofglucose intolerance [253] In the skeletal muscle of rats fedan HFD for 8 weeks the insulin-induced glucose uptakeis impaired [254] FFAs have been considered the factorsresponsible for HFD-induced leptin and insulin resistance[255ndash257]

43 Hepatic Insulin Resistance and Vicious Cycle The liverplays an essential role in the control of glucose andlipid homeostasis It coordinately regulates the processesin responses to nutritional and hormonal stimuli Insulinplays a major role in directing the liverrsquos metabolic status[258] which is partially attributed to the regulation of theexpression of genes involved in hepatic glucose and lipidmetabolism [215 259]

Insulin controls the expression of a variety of genesinvolved in glycolysis glycogenesis and lipogenesis andgluconeogenesis in the liver [145] Generally hepatic lipidand glucose metabolism is altered with the development ofinsulin resistance in obesity and NIDDM [258] This canbe reflected in the expression of insulin-regulated hepaticgenes for glucose and FA metabolism When the liver isinsulin sensitive insulin stimulates lipogenesis and inhibitsgluconeogenesis For example to regulate hepatic glucosehomeostasis insulin increases the expression of Gck gene[119 120] and Srebp-1c [224] a family member of SREBPswhich regulate the hepatic cholesterol and FA biosynthesisand their homeostasis [260] It suppresses the expressionof Pck1 [142] and G6pc [145] which control the first andlast steps of gluconeogenesis respectively When the liver isinsulin resistant insulin no longer inhibits gluconeogenesisHowever the liver still keeps the elevated lipogenesis Theelevated FA biosynthesis in the insulin-resistant state furtherfacilitates insulin secretion from pancreatic 120573-cells whichprobably enhances lipogenesis and results in a vicious cycle[113 261] The coexistence of the hepatic insulin resistanceand sensitivity at the gene expression level has been observedin rodent obese and diabetic models [215 258] Howeverthe mechanism of this coexistence of insulin sensitivity andresistance has not been revealed [261]

Recently the SREBP cleavage-activating protein gene(Scap) an escort protein necessary for generating nuclearforms of SREBPs has been knocked out in insulin-resistantobob mice [262] Deficiency of hepatic Scap reverses liverlipogenesis and steatosis in obobmice However the plasmalevels of glucose and insulin and the hepatic expression levelsof Pck1 andG6pcwere not different between the control obobmice and the obob mice with liver-specific Scap knockout[262] It seems that the suppression of hepatic FA synthesis

12 ISRN Hepatology

is not sufficient to correct insulin resistance Whether otherfactors play a role in the hepatic insulin resistance is still anopen question

The clinical use of RA-based medicine such asisotretinoin (13-cis RA) caused elevation of plasma TGlevels in human subjects [195ndash197] This increase in plasmaTG levels is also observed in rats [201ndash203] From our VAstatus studies we have shown that VA status affected theobesity development in ZF rats and reduced plasma insulinand TG levels in ZL and ZF rats suggesting improvement ofinsulin sensitivity [116] The hepatic expression of Srebp-1cwas reduced in VA-deficient animals [116] RA synergizeswith insulin to induce the expression of Srebp-1c in primaryrat hepatocytes [227] On the other hand RA treatmentinduces Pck1 expression and attenuates insulin-mediatedsuppression of its expression in primary rat hepatocytes [172]All of these observations demonstrate that RA attenuatesinsulin action (insulin-suppressed Pck1 expression) andstill promotes insulin action (insulin-induced Srebp-1cexpression) in the same primary hepatocytes

44 Possible Mechanism by Which RA Production Causes theDevelopment of the Vicious Cycle in Hepatocytes Could RAor other metabolites from VA catabolism be a factor thatcontributes to the hepatic insulin resistance and the viciouscycleUsing the regulation ofPck1 and Srebp-1c as themodel Ihave come upwith the following scheme to show that retinoidmetabolism could be a factor that causes the vicious cycle inthe liver As shown in Figure 3(a) in insulin-sensitive hepa-tocytes RA derived from retinal coordinates with insulin toregulate the expression of Srebp-1c and Pck1 The SREBP-1cprotein is processed to mature form a step that can be facili-tated by insulin [263] The mature form of SREBP-1c entersinto the nucleus and induces the mRNA levels of Raldh1and Fas which are respectively transcribed into RALDH1and FAS RALDH1 catalyzes the conversion of retinal to RAFAS catalyzes the synthesis of palmitate which is esterifiedinto TGs or elongated to longer FAs The Pck1 mRNA isused to translate into PEPCK-C protein which contributesto glucogenogenesis In the insulin-resistant hepatocytes asshown in Figure 3(b) the elevation of Raldh1 expressiondue to leptin deficiency [45] or induction of SREBP-1c byhigh-cholesterol feeding [232] induces the production of RAThe elevated RA levels will stimulate the transcription ofSrebp-1c and Pck1 This leads to more production of SREBP-1c and its mature form in the presence of higher insulinlevels in the insulin-resistant state The induction of SREBP-1c further enhances the transcription of Raldh1 and Fas andtheir corresponding proteins for the production of moreRAs and FAs respectively The RA production and SREBP-1c expression form a feed-forward cycle which causes moreTG and RA production in the insulin-resistant liver At thesame time more of the PEPCK-C protein is generated dueto the elevated Pck1 transcription by RA stimulation whichis not responsive to insulin inhibition as we have shown in[172] This leads to elevated gluconeogenesis in the insulin-resistant liver Eventually the phenotypes appear as if insulin

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1cRetinal

RALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(a) Insulin-sensitive hepatocytes

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1c

RetinalRALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(b) Insulin-resistant hepatocytes

Figure 3 The effects of RA on the insulin-regulated Srebp-1cand Pck1 expression levels the protein levels of SREBP-1c theexpression levels of Raldh1 and Fas and the fatty acid synthesisand gluconeogenesis in insulin-sensitive (a) and insulin-resistant (b)hepatocytes Please see the text in this paper for description Uparrows next to the text indicate induction The intensified weight ofthe lines indicates the induction of that part of the pathway

no longer suppresses gluconeogenesis while it still stimulatesFA synthesis in the insulin-resistant state

5 Perspectives and Future Directions

I have proposed a mechanism by which VA metabolismcontributes to the development of hepatic insulin resistanceIt explains some observations reported in the previous studiesof rodent obese and diabetic models [215 258] However itleavesmore open questionsThefirst one iswhat the initiationfactor is So far the elevated expression of Raldh1 mRNA inthe liver has been observed in ZF rats [45] and mice fed ahigh-cholesterol diet [232] These two conditions cause a lotof physiological changes such as overfeeding in ZF rats andchange of cholesterol biosynthesis in response to the feedingof high-cholesterol diet Knocking down Raldh1 specificallyin hepatocytes is needed to answer these questions The

ISRN Hepatology 13

second question is whether RA synthesis in hepatocytesis a regulated process in response to dietary or hormonalstimulations If Raldh1 is a downstream gene of SREBP-1cit should be regulated when the SREBP-1c level changes Asthe expression of Srebp-1c responds to insulin stimulation andoxysterols the regulation of Raldh1 expression in the livershould be studied The third question is why it is RALDH1but not other RALDHs Specific inhibitors of RALDHsmay be needed to answer this question Last question iswhether we can attenuate insulin resistance by suppressingthe RALDH1 activity in the liver It has been shown thatRaldh1minusminus mice are still insulin sensitive when they are onan HFD [26] This has been attributed to the effects on theadipogenesis However the liver of those knockout mice hasreduced lipid synthesis [231] Further studies are warrantedto answer all of these questions Hopefully it can become anintervention point for the treatment of insulin resistance andmetabolic diseases

Acknowledgments

This work was financially supported by a research grantfrom Allen Foundation Inc (to Guoxun Chen) a start-up fund from the University of Tennessee at Knoxville (toGuoxun Chen) and a Scientist Development Grant fromthe AmericanHeart Association (09SDG2140003 to GuoxunChen) The author thanks his colleague Dr Lauren Gellar forreading through this paper and offering her edits

References

[1] F G Hopkins ldquoFeeding experiments illustrating the impor-tance of accessory factors in normal dietariesrdquo The Journal ofPhysiology vol 44 no 5-6 pp 425ndash460 1912

[2] K J Carpenter ldquoA short history of nutritional science part 3(1912ndash1944)rdquo Journal of Nutrition vol 133 no 10 pp 3023ndash30322003

[3] E V McCollum and M Davis ldquoThe necessity of certain lipinsin the diet during growthrdquo Journal of Biological Chemistry vol15 no 1 pp 167ndash175 1913

[4] T B Osborne and L B Mendel ldquoFeeding experiments with fat-free food mixturesrdquo Journal of Biological Chemistry vol 12 no1 pp 81ndash89 1912

[5] R D Semba ldquoOn the lsquoDiscoveryrsquo of Vitamin Ardquo Annals ofNutrition and Metabolism vol 61 no 3 pp 192ndash198 2012

[6] R Blomhoff and H K Blomhoff ldquoOverview of retinoidmetabolism and functionrdquo Journal of Neurobiology vol 66 no7 pp 606ndash630 2006

[7] A Sommer ldquoVitamin A deficiency and clinical disease anhistorical overviewrdquo Journal of Nutrition vol 138 no 10 pp1835ndash1839 2008

[8] K J Rothman L L Moore M R Singer U-S Nguyen SMannino and A Milunsky ldquoTeratogenicity of high vitamin Aintakerdquo The New England Journal of Medicine vol 333 no 21pp 1369ndash1373 1995

[9] S Bershad A Rubinstein and J R Paterniti Jr ldquoChanges inplasma lipids and lipoproteins during isotretinoin therapy foracnerdquoThe New England Journal of Medicine vol 313 no 16 pp981ndash985 1985

[10] N Rodondi R Darioli A-A Ramelet et al ldquoHigh risk forhyperlipidemia and the metabolic syndrome after an episodeof hypertriglyceridemia during 13-cis retinoic acid therapy foracne a pharmacogenetic studyrdquo Annals of Internal Medicinevol 136 no 8 pp 582ndash589 2002

[11] H-U Klor A Weizel M Augustin et al ldquoThe impact oforal vitamin A derivatives on lipid metabolism what recom-mendations can be derived for dealing with this issue in thedaily dermatological practicerdquo Journal of the German Societyof Dermatology vol 9 no 8 pp 600ndash607 2011

[12] R M Russell ldquoThe vitamin A spectrum from deficiency totoxicityrdquoThe American Journal of Clinical Nutrition vol 71 no4 pp 878ndash884 2000

[13] A C Ross B Caballero R J Cousins K L Tucker and T RZiegler Modern Nutrition in Health and Diseases 11th edition2012

[14] E H Harrison ldquoMechanisms of digestion and absorption ofdietary vitamin Ardquo Annual Review of Nutrition vol 25 no 1pp 87ndash103 2005

[15] M R Lakshman ldquoAlpha and omega of carotenoid cleavagerdquoJournal of Nutrition vol 134 no 1 pp 241ndash245 2004

[16] I Potrykus ldquoNutritionally enhanced rice to combat malnutri-tion disorders of the poorrdquo Nutrition Reviews vol 61 no 6 ppS101ndashS104 2003

[17] A Wyss ldquoCarotene oxygenases a new family of double bondcleavage enzymesrdquo Journal of Nutrition vol 134 no 1 pp 246ndash250 2004

[18] R Kawaguchi J Yu J Honda et al ldquoA membrane receptor forretinol binding protein mediates cellular uptake of vitamin ArdquoScience vol 315 no 5813 pp 820ndash825 2007

[19] P Alapatt F Guo S M Komanetsky et al ldquoLiver retinoltransporter and receptor for serum retinol-binding protein(RBP4)rdquo Journal of Biological Chemistry vol 288 no 2 pp1250ndash1265 2013

[20] A R Moise N Noy K Palczewski and W S Blaner ldquoDeliveryof retinoid-based therapies to target tissuesrdquo Biochemistry vol46 no 15 pp 4449ndash4458 2007

[21] G Duester ldquoFamilies of retinoid dehydrogenases regulatingvitamin A function Production of visual pigment and retinoicacidrdquo European Journal of Biochemistry vol 267 no 14 pp4315ndash4324 2000

[22] M Theodosiou V Laudet and M Schubert ldquoFrom carrotto clinic an overview of the retinoic acid signaling pathwayrdquoCellular andMolecular Life Sciences vol 67 no 9 pp 1423ndash14452010

[23] J L Napoli ldquoInteractions of retinoid binding proteins andenzymes in retinoidmetabolismrdquoBiochimica et BiophysicaActavol 1440 no 2-3 pp 139ndash162 1999

[24] X Chai M H E M Boerman Y Zhai and J L NapolildquoCloning of a cDNA for liver microsomal retinol dehydro-genase A tissue-specific short-chain alcohol dehydrogenaserdquoJournal of Biological Chemistry vol 270 no 8 pp 3900ndash39041995

[25] B X Wu G Moiseyev Y Chen B Rohrer R K Crouch andJ-XMa ldquoIdentification of RDH10 an all-trans retinol dehydro-genase in retinal Muller cellsrdquo Investigative Ophthalmology andVisual Science vol 45 no 11 pp 3857ndash3862 2004

[26] O Ziouzenkova G Orasanu M Sharlach et al ldquoRetinalde-hyde represses adipogenesis and diet-induced obesityrdquo NatureMedicine vol 13 no 6 pp 695ndash702 2007

14 ISRN Hepatology

[27] J L Napoli ldquoPhysiological insights into all-trans-retinoic acidbiosynthesisrdquo Biochimica et Biophysica Acta vol 1821 no 1 pp152ndash167 2012

[28] G Wolf ldquoTissue-specific increases in endogenous all-transretinoic acid possible contributing factor in ethanol toxicityrdquoNutrition Reviews vol 68 no 11 pp 689ndash692 2010

[29] P V Bhat J Labrecque JM Boutin A Lacroix andA YoshidaldquoCloning of a cDNA encoding rat aldehyde dehydrogenase withhigh activity for retinal oxidationrdquoGene vol 166 no 2 pp 303ndash306 1995

[30] M Lin M Zhang M Abraham S M Smith and J LNapoli ldquoMouse retinal dehydrogenase 4 (RALDH4) molecularcloning cellular expression and activity in 9-cis-retinoic acidbiosynthesis in intact cellsrdquo Journal of Biological Chemistry vol278 no 11 pp 9856ndash9861 2003

[31] F A Mic A Molotkov X Fan A E Cuenca and GDuester ldquoRALDH3 a retinaldehyde dehydrogenase that gener-ates retinoic acid is expressed in the ventral retina otic vesicleand olfactory pit during mouse developmentrdquo Mechanisms ofDevelopment vol 97 no 1-2 pp 227ndash230 2000

[32] X Wang P Penzes and J L Napoli ldquoCloning of a cDNAencoding an aldehyde dehydrogenase and its expression inEscherichia coli recognition of retinal as substraterdquo Journal ofBiological Chemistry vol 271 no 27 pp 16288ndash16293 1996

[33] A Molotkov and G Duester ldquoGenetic evidence that retinalde-hyde dehydrogenase Raldh1 (Aldh1a1) functions downstreamof alcohol dehydrogenase Adh1 in metabolism of retinol toretinoic acidrdquo Journal of Biological Chemistry vol 278 no 38pp 36085ndash36090 2003

[34] G Elizondo J Corchero E Sterneck and F J GonzalezldquoFeedback inhibition of the retinaldehyde dehydrogenase geneALDH1 by retinoic acid through retinoic acid receptor 120572and CCAATenhancer-binding protein 120573rdquo Journal of BiologicalChemistry vol 275 no 50 pp 39747ndash39753 2000

[35] G Elizondo I M Medina-Dıaz R Cruz F J Gonzalez and LVega ldquoRetinoic acid modulates retinaldehyde dehydrogenase 1gene expression through the induction of GADD153-CEBP120573interactionrdquo Biochemical Pharmacology vol 77 no 2 pp 248ndash257 2009

[36] K Fujiwara M Kikuchi K Horiguchi et al ldquoEstrogen receptoralpha regulates retinaldehyde dehydrogenase 1 expression in ratanterior pituitary cellsrdquo Endocrine Journal vol 56 no 8 pp963ndash973 2009

[37] K Fujiwara F Maekawa M Kikuchi S Takigami T Yadaand T Yashiro ldquoExpression of retinaldehyde dehydrogenase(RALDH)2 and RALDH3 but not RALDH1 in the developinganterior pituitary glands of ratsrdquo Cell and Tissue Research vol328 no 1 pp 129ndash135 2007

[38] GWolf ldquoThe enzymatic cleavage of 120573-carotene still controver-sialrdquo Nutrition Reviews vol 53 no 5 pp 134ndash137 1995

[39] S Abu-Abed P Dolle D Metzger B Beckett P Chambonand M Petkovich ldquoThe retinoic acid-metabolizing enzymeCYP26A1 is essential for normal hindbrain patterning verte-bral identity and development of posterior structuresrdquo Genesand Development vol 15 no 2 pp 226ndash240 2001

[40] M A Leo S Iida and C S Lieber ldquoRetinoic acid metabolismby a system reconstituted with cytochrome P-450rdquo Archives ofBiochemistry and Biophysics vol 234 no 1 pp 305ndash312 1984

[41] MA Leo JM Lasker J L Raucy C-I KimM Black andC SLieber ldquoMetabolism of retinol and retinoic acid by human livercytochrome P450IIC8rdquoArchives of Biochemistry and Biophysicsvol 269 no 1 pp 305ndash312 1989

[42] R Quere A Baudet B Cassinat et al ldquoPharmacogenomicanalysis of acute promyelocytic leukemia cells highlightsCYP26cytochrome metabolism in differential all-trans retinoic acidsensitivityrdquo Blood vol 109 no 10 pp 4450ndash4460 2007

[43] J AWhite B Beckett-Jones Y-D Guo et al ldquocDNA cloning ofhuman retinoic acid-metabolizing enzyme (hP450RAI) identi-fies a novel family of cytochromes p450 (CYP26)rdquo Journal ofBiological Chemistry vol 272 no 30 pp 18538ndash18541 1997

[44] Y Zhang R Zolfaghari Reza and A C Ross ldquoMultiple retinoicacid response elements cooperate to enhance the inducibility ofCYP26A1 gene expression in liverrdquo Gene vol 464 no 1-2 pp32ndash43 2010

[45] Y Li Y Zhang R Li et al ldquoThe hepatic raldh1 expression iselevated in Zucker fatty rats and its over-expression introducedthe retinal-induced Srebp-1c expression in INS-1 cellsrdquo PLoSONE vol 7 no 9 Article ID e45210 2012

[46] R M Evans ldquoThe nuclear receptor superfamily a Rosetta stonefor physiologyrdquo Molecular Endocrinology vol 19 no 6 pp1429ndash1438 2005

[47] P Chambon ldquoA decade of molecular biology of retinoic acidreceptorsrdquo FASEB Journal vol 10 no 9 pp 940ndash954 1996

[48] D J Mangelsdorf and RM Evans ldquoThe RXR heterodimers andorphan receptorsrdquo Cell vol 83 no 6 pp 841ndash850 1995

[49] J E Balmer and R Blomhoff ldquoA robust characterization ofretinoic acid response elements based on a comparison of sitesin three speciesrdquo Journal of Steroid Biochemistry and MolecularBiology vol 96 no 5 pp 347ndash354 2005

[50] R Kurokawa J DiRenzo M Boehm et al ldquoRegulation ofretinoid signalling by receptor polarity and allosteric control ofligand bindingrdquo Nature vol 371 no 6497 pp 528ndash531 1994

[51] A Cvekl and W-L Wang ldquoRetinoic acid signaling in mam-malian eye developmentrdquo Experimental Eye Research vol 89no 3 pp 280ndash291 2009

[52] V Dupe M Davenne J Brocard et al ldquoIn vivo functional anal-ysis of the Hoxa-1 31015840 retinoic acid response element (31015840RARE)rdquoDevelopment vol 124 no 2 pp 399ndash410 1997

[53] A C Ross ldquoRetinoid production and catabolism role of dietin regulating retinol esterification and retinoic acid oxidationrdquoJournal of Nutrition vol 133 no 1 pp 291ndash296 2003

[54] T Moore and P D Holmes ldquoThe production of experimentalvitamin A deficiency in rats andmicerdquo Laboratory Animals vol5 no 2 pp 239ndash250 1971

[55] A C Ross and E H Harrison ldquoVitamin A and carotenoidsrdquoin Handbook of Vitamins D E McCormick R R Rucker J WSuttie et al Eds CRC Press Boca Raton Fla USA 4th edition2006

[56] A Chawta J J Repa R M Evans and D J MangelsdorfldquoNuclear receptors and lipid physiology opening the x-filesrdquoScience vol 294 no 5548 pp 1866ndash1870 2001

[57] C K Glass and M G Rosenfeld ldquoThe coregulator exchangein transcriptional functions of nuclear receptorsrdquo Genes andDevelopment vol 14 no 2 pp 121ndash141 2000

[58] A L Bookout Y Jeong M Downes R T Yu R M EvansandD JMangelsdorf ldquoAnatomical profiling of nuclear receptorexpression reveals a hierarchical transcriptional networkrdquo Cellvol 126 no 4 pp 789ndash799 2006

[59] B Mascrez M Mark W Krezel et al ldquoDifferential contribu-tions of AF-1 andAF-2 activities to the developmental functionsof RXR120572rdquo Development vol 128 no 11 pp 2049ndash2062 2001

[60] D Li T Li F Wang H Tian and H H Samuels ldquoFunctionalevidence for retinoid X receptor (RXR) as a nonsilent partner

ISRN Hepatology 15

in the thyroid hormone receptorRXR heterodimerrdquoMolecularand Cellular Biology vol 22 no 16 pp 5782ndash5792 2002

[61] F M Sladek W Zhong E Lai and J E Darnell Jr ldquoLiver-enriched transcription factor HNF-4 is a novel member ofthe steroid hormone receptor superfamilyrdquo Genes and Develop-ment vol 4 no 12 pp 2353ndash2365 1990

[62] K Yamagata H Furuta N Oda et al ldquoMutations in thehepatocyte nuclear factor-4120572 gene inmaturity-onset diabetes ofthe young (MODY1)rdquo Nature vol 384 no 6608 pp 458ndash4601996

[63] M Stoffel and S ADuncan ldquoThematurity-onset diabetes of theyoung (MODY1) transcription factor HNF4120572 regulates expres-sion of genes required for glucose transport and metabolismrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 24 pp 13209ndash13214 1997

[64] M Lehto P-O Bitzen B Isomaa et al ldquoMutation in the HNF-4120572 gene affects insulin secretion and triglyceride metabolismrdquoDiabetes vol 48 no 2 pp 423ndash425 1999

[65] G P Hayhurst Y-H Lee G Lambert J M Ward and F JGonzalez ldquoHepatocyte nuclear factor 4120572 (Nuclear receptor 2A1)is essential formaintenance of hepatic gene expression and lipidhomeostasisrdquo Molecular and Cellular Biology vol 21 no 4 pp1393ndash1403 2001

[66] U Roth K Jungermann and T Kietzmann ldquoActivation ofglucokinase gene expression by hepatic nuclear factor 4120572 inprimary hepatocytesrdquo Biochemical Journal vol 365 no 1 pp223ndash228 2002

[67] S Mandard R Stienstra P Escher et al ldquoGlycogen synthase2 is a novel target gene of peroxisome proliferator-activatedreceptorsrdquo Cellular and Molecular Life Sciences vol 64 no 9pp 1145ndash1157 2007

[68] F Rajas A Gautier I Bady S Montano and G MithieuxldquoPolyunsaturated fatty acyl coenzyme a suppress the glucose-6-phosphatase promoter activity bymodulating the DNA bindingof hepatocyte nuclear factor 4120572rdquo Journal of Biological Chemistryvol 277 no 18 pp 15736ndash15744 2002

[69] B Viollet A Kahn and M Raymondjean ldquoProtein kinase A-dependent phosphorylation modulates DNA-binding activityof hepatocyte nuclear factor 4rdquoMolecular and Cellular Biologyvol 17 no 8 pp 4208ndash4219 1997

[70] L Palanker J M Tennessen G Lam and C S Thum-mel ldquoDrosophila HNF4 regulates lipid mobilization and 120573-oxidationrdquo Cell Metabolism vol 9 no 3 pp 228ndash239 2009

[71] A Miura K Yamagata M Kakei et al ldquoHepatocyte nuclearfactor-4120572 is essential for glucose-stimulated insulin secretion bypancreatic 120573-cellsrdquo Journal of Biological Chemistry vol 281 no8 pp 5246ndash5257 2006

[72] R Bartoov-Shifman R Hertz H Wang C B Wollheim JBar-Tana and M D Walker ldquoActivation of the insulin genepromoter through a direct effect of hepatocyte nuclear factor4120572rdquo Journal of Biological Chemistry vol 277 no 29 pp 25914ndash25919 2002

[73] H Wang P Maechler P A Antinozzi K A Hagenfeldt andC B Wollheim ldquoHepatocyte nuclear factor 4120572 regulates theexpression of pancreatic 120573-cell genes implicated in glucosemetabolism and nutrient-induced insulin secretionrdquo Journal ofBiological Chemistry vol 275 no 46 pp 35953ndash35959 2000

[74] K Reue T Leff and J L Breslow ldquoHuman apolipoproteinCIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factorsrdquo Journal ofBiological Chemistry vol 263 no 14 pp 6857ndash6864 1988

[75] T Leff K Reue A Melian H Culver and J L BreslowldquoA regulatory element in the apoCIII promoter that directshepatic specific transcription binds to proteins in expressingand nonexpressing cell typesrdquo Journal of Biological Chemistryvol 264 no 27 pp 16132ndash16137 1989

[76] S N Lavrentiadou M Hadzopoulou-Cladaras D Kardassisand V I Zannis ldquoBinding specificity and modulation of thehuman apocIII promoter activity by heterodimers of ligand-dependent nuclear receptorsrdquo Biochemistry vol 38 no 3 pp964ndash975 1999

[77] T R Magee Y Cai M E El-Houseini J Locker and Y-JY Wan ldquoRetinoic acid mediates down-regulation of the 120572-fetoprotein gene through decreased expression of hepatocytenuclear factorsrdquo Journal of Biological Chemistry vol 273 no 45pp 30024ndash30032 1998

[78] A Qian Y Cai T R Magee and Y J Y Wan ldquoIdentificationof retinoic acid-responsive elements on the HNF1alpha andHNF4alpha genesrdquo Biochemical and Biophysical Research Com-munications vol 276 no 3 pp 837ndash842 2000

[79] H Nakshatri and P Chambon ldquoThe directly repeatedRG(GT)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites forRAR RXR HNF-4 and ARP-1 homo- and heterodimersrdquoJournal of Biological Chemistry vol 269 no 2 pp 890ndash9021994

[80] T Makita G Hernandez-Hoyos T H-P Chen H Wu E VRothenberg and H M Sucov ldquoA developmental transition indefinitive erythropoiesis erythropoietin expression is sequen-tially regulated by retinoic acid receptors andHNF4rdquoGenes andDevelopment vol 15 no 7 pp 889ndash901 2001

[81] T I Kambe J Tada-Kambe Y Kuge Y Yamaguchi-Iwai MNagao and R Sasaki ldquoRetinoic acid stimulates erythropoietingene transcription in embryonal carcinoma cells through thedirect repeat of a steroidthyroid hormone receptor responseelement half-site in the hypoxia-response enhancerrdquo Blood vol96 no 9 pp 3265ndash3271 2000

[82] F-J Lin J Qin K Tang S Y Tsai and M-J Tsai ldquoCoup drsquoEtatan orphan takes controlrdquo Endocrine Reviews vol 32 no 3 pp404ndash421 2011

[83] L-H Wang S Y Tsai R G Cook W G Beattie M-J Tsaiand BW OrsquoMalley ldquoCOUP transcription factor is a member ofthe steroid receptor superfamilyrdquoNature vol 340 no 6229 pp163ndash166 1989

[84] X Leng A J Cooney S Y Tsai and M-J Tsai ldquoMolecularmechanisms of COUP-TF-mediated transcriptional repressionevidence for transrepression and active repressionrdquo Molecularand Cellular Biology vol 16 no 5 pp 2332ndash2340 1996

[85] L Li X Xie J Qin et al ldquoThe nuclear orphan receptorCOUP-TFII plays an essential role in adipogenesis glucosehomeostasis and energy metabolismrdquo Cell Metabolism vol 9no 1 pp 77ndash87 2009

[86] F A Pereira Q Yuhong G Zhou M-J Tsai and S YTsai ldquoThe orphan nuclear receptor COUP-TFII is required forangiogenesis and heart developmentrdquo Genes and Developmentvol 13 no 8 pp 1037ndash1049 1999

[87] N Takamoto I Kurihara K Lee F J DeMayo M-J Tsai andS Y Tsai ldquoHaploinsufficiency of chicken ovalbumin upstreampromoter transcription factor II in female reproductionrdquoMolec-ular Endocrinology vol 19 no 9 pp 2299ndash2308 2005

[88] P Zhang M Bennoun C Gogard et al ldquoExpression of COUP-TFII in metabolic tissues during developmentrdquo Mechanisms ofDevelopment vol 119 no 1 pp 109ndash114 2002

16 ISRN Hepatology

[89] Z Xu S Yu C-H Hsu J Eguchi and E D Rosen ldquoTheorphan nuclear receptor chicken ovalbumin upstream pro-moter-transcription factor II is a critical regulator of adipogene-sisrdquoProceedings of theNationalAcademy of Sciences of theUnitedStates of America vol 105 no 7 pp 2421ndash2426 2008

[90] P Bardoux P Zhang D Flamez et al ldquoEssential role of chickenovalbumin upstreampromoter-transcription factor II in insulinsecretion and insulin sensitivity revealed by conditional geneknockoutrdquo Diabetes vol 54 no 5 pp 1357ndash1363 2005

[91] G Achatz B Holzl R Speckmayer C Hauser F Sandhoferand B Paulweber ldquoFunctional domains of the human orphanreceptor ARP-1COUP-TFII involved in active repression andtransrepressionrdquo Molecular and Cellular Biology vol 17 no 9pp 4914ndash4932 1997

[92] S A Kliewer K Umesono R A Heyman D J MangelsdorfJ A Dyck and R M Evans ldquoRetinoid X receptor-COUP-TFinteractionsmodulate retinoic acid signalingrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol89 no 4 pp 1448ndash1452 1992

[93] A J Cooney S Y Tsai BW OrsquoMalley andM-J Tsai ldquoChickenovalbumin upstreampromoter transcription factor (COUP-TF)dimers bind to different GGTCA response elements allowingCOUP-TF to repress hormonal induction of the vitamin D3thyroid hormone and retinoic acid receptorsrdquo Molecular andCellular Biology vol 12 no 9 pp 4153ndash4163 1992

[94] SW Kruse K Suino-Powell X E Zhou et al ldquoIdentification ofCOUP-TFII orphannuclear receptor as a retinoic acid-activatedreceptorrdquo PLoS Biology vol 6 no 9 Article ID e227 2008

[95] J P Berger T E Akiyama and P T Meinke ldquoPPARs thera-peutic targets for metabolic diseaserdquo Trends in PharmacologicalSciences vol 26 no 5 pp 244ndash251 2005

[96] JM Peters andF J Gonzalez ldquoSorting out the functional role(s)of peroxisome proliferator-activated receptor-120573120575 (PPAR120573120575)in cell proliferation and cancerrdquo Biochimica et Biophysica Actavol 1796 no 2 pp 230ndash241 2009

[97] A Tenenbaum and E Fisman ldquoBalanced pan-PPAR activatorbezafibrate in combination with statin comprehensive lipidscontrol and diabetes preventionrdquo Cardiovascular Diabetologyvol 11 no 1 article 140 2012

[98] O Braissant F Foufelle C Scotto M Dauca and W WahlildquoDifferential expression of peroxisome proliferator-activatedreceptors (PPARs) tissue distribution of PPAR-120572 -120573 and -120574 inthe adult ratrdquo Endocrinology vol 137 no 1 pp 354ndash366 1996

[99] H Higashiyama A N Billin Y Okamoto M Kinoshita andS Asano ldquoExpression profiling of Peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues usingtissue microarrayrdquo Histochemistry and Cell Biology vol 127 no5 pp 485ndash494 2007

[100] P S Jones R Savory P Barratt et al ldquoChromosomal local-isation inducibility tissue-specific expression and strain dif-ferences in three murine peroxisome-proliferator-activated-receptor genesrdquo European Journal of Biochemistry vol 233 no1 pp 219ndash226 1995

[101] S A Kliewer B M Forman B Blumberg et al ldquoDifferentialexpression and activation of a family of murine peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no15 pp 7355ndash7359 1994

[102] E E Girroir H E Hollingshead P He B Zhu G H Perdewand J M Peters ldquoQuantitative expression patterns of peroxi-some proliferator-activated receptor-120573120575 (PPAR120573120575) protein in

micerdquo Biochemical and Biophysical Research Communicationsvol 371 no 3 pp 456ndash461 2008

[103] P Escher O Braissant S Basu-Modak L Michalik W Wahliand B Desvergne ldquoRat PPARs quantitative analysis in adult rattissues and regulation in fasting and refeedingrdquo Endocrinologyvol 142 no 10 pp 4195ndash4202 2001

[104] D Auboeuf J Rieusset L Fajas et al ldquoTissue distributionand quantification of the expression of mRNAs of peroxi-some proliferator-activated receptors and liver X receptor-120572 inhumans no alteration in adipose tissue of obese and NIDDMpatientsrdquo Diabetes vol 46 no 8 pp 1319ndash1327 1997

[105] N ShawM Elholm andN Noy ldquoRetinoic acid is a high affinityselective ligand for the peroxisome proliferator-activated recep-tor 120573120575rdquo Journal of Biological Chemistry vol 278 no 43 pp41589ndash41592 2003

[106] G Wolf ldquoRetinoic acid as cause of cell proliferation or cellgrowth inhibition depending on activation of one of twodifferent nuclear receptorsrdquoNutrition Reviews vol 66 no 1 pp55ndash59 2008

[107] T T Schug D C Berry N S Shaw S N Travis and N NoyldquoOpposing effects of retinoic acid on cell growth result fromalternate activation of two different nuclear receptorsrdquo Cell vol129 no 4 pp 723ndash733 2007

[108] D C Berry and N Noy ldquoAll-trans-retinoic acid repressesobesity and insulin resistance by activating both peroxisomeproliferation-activated receptor 120573120575 and retinoic acid receptorrdquoMolecular and Cellular Biology vol 29 no 12 pp 3286ndash32962009

[109] D C Berry D DeSantis H Soltanian C M Croniger andN Noy ldquoRetinoic acid upregulates preadipocyte genes to blockadipogenesis and suppress diet-induced obesityrdquo Diabetes vol61 no 5 pp 1112ndash1121 2012

[110] M G Borland C Khozoie P P Albrecht et al ldquoStableover-expression of PPAR120573120575 and PPAR120574 to examine receptorsignaling in human HaCaT keratinocytesrdquo Cellular Signallingvol 23 no 12 pp 2039ndash2050 2011

[111] S E OrsquoSullivan and D A Kendall ldquoCannabinoid activationof peroxisome proliferator-activated receptors potential formodulation of inflammatory diseaserdquo Immunobiology vol 215no 8 pp 611ndash616 2010

[112] Z C Yan D Y Liu L L Zhang et al ldquoExercise reduces adiposetissue via cannabinoid receptor type 1 which is regulated byperoxisome proliferator-activated receptor-120575rdquo Biochemical andBiophysical Research Communications vol 354 no 2 pp 427ndash433 2007

[113] J D McGarry ldquoWhat if Minkowski had been ageusic Analternative angle on diabetesrdquo Science vol 258 no 5083 pp766ndash770 1992

[114] TMoore ldquoVitaminA and carotene the vitaminA reserve of theadult human being in health and diseaserdquo Biochemical Journalvol 31 no 1 pp 155ndash164 1937

[115] GWolfMD Lane and B C Johnson ldquoStudies on the functionof vitamin A in metabolismrdquo Journal of Biological Chemistryvol 225 no 2 pp 995ndash1008 1957

[116] Y Zhang R Li Y Li W Chen S Zhao and G Chen ldquoVitaminA status affects obesity development and hepatic expression ofkey genes for fuel metabolism in Zucker fatty ratsrdquoBiochemistryand Cell Biology vol 90 no 4 pp 548ndash557 2012

[117] M Singh V N Singh and T A Venkitasubramanian ldquoEarlyeffects of feeding excess vitamin A hepatic glycogen bloodlactic acid plasma nefa and glucose tolerance in ratsrdquo LifeSciences vol 7 no 5 pp 239ndash247 1968

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Hepatology 9

aVADdiet at weaning (21 days old) formore than 9weeks hadreduction of carcass fat but not cholesterol content [183] Onthe other hand this reduction of body fat was not observedin the rats of the pair-feeding group which were given thesame amount of a VAS diet in weight and calories as theone consumed by the VAD rats [183] These results indicatethat the reduction of food intake alone could not be used toexplain the depletion of body fat in the VAD rats

The VA status also seems to affect the hepatic expressionof apo AI mRNA The expression of hepatic apo AI hasbeen shown to be sensitive to VA status [184] When theLewis strain rats develop VA deficiency the expression levelof hepatic but not intestinal apo AI mRNA is elevated Thisinduction is dropped upon single dosage of RA treatment[184] On the other hand in the intestine and liver of VA-deficient Wistar rats both all-trans RA and 9-cis RA caninduce apo AI mRNA levels [185] The same treatment canonly induce the mRNA level of apo CIII in the intestine butnot in the liver [185] In humans the plasma VA levels arepositively correlated with the elevations of proteins of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiapatients [186]

When male Wistar rats were fed a VAD diet for 3 monthsafter weaning (21 days old) they had lower plasma TGs andcholesterol levels than the control ones fed a VAS diet [187]When the hepatic synthesis of FAs and phospholipids wasanalyzed in the liver slices the incorporations of [14C]cholineinto phosphatidylcholine and [14C]acetate into FAs were alsoreduced in the VAD rats compared with their VAS controls[187] The VAD rats had lower activities and mRNA levels ofacetyl-CoA carboxylase but higher activity and mRNA levelof carnitine palmitoyltransferase-I than VAS rats had [187]These results demonstrate that there is a reduction of hepaticfatty acid synthesis along with an induction of hepatic fattyacid oxidation in the liver of VAD rats

My lab has conducted experiments and shown that VAstatus affects the obesity development in ZF rats and controlsplasma TG levels in ZL and ZF rats [116] ZF rats a ratmodel of obesity development [188] develop obesity dueto a missense mutation in the extracellular domain of allleptin receptor isoforms [189ndash191] They have been used forthe studies of obesity insulin resistance and other aspectsof metabolic diseases [192 193] We have analyzed growthplasma parameters and expression levels of hepatic genes ofmale ZL and ZF rats fed a VAD or a VAS diet at weaning(21 days of age) for 8 weeks Body masses of ZL and ZF ratsfed the VAD diet are lower than those of their correspondingcontrols fed the VAS diet at the end of the feeding periodThe VAD ZL or ZF rats begin to take less food than the VASones after five weeks on the diet The VAD ZL or ZF rats havelower plasma glucose TG insulin and leptin levels than theircorresponding VAS rats have The liver glycogen content netweights of epididymal fat and liver and fat-to-body massratio (ZL only) in the VAD rats are also lower than those inthe VAS ones [116] This demonstrates that VA status affectsplasma TG levels in both ZF and ZL rats and the obesitydevelopment in ZF rats This phenomenon may be caused by

the combination of VA deficiency and hypoinsulinemia sinceinsulin secretion is impaired in the VAD rats [194]

32 The Development of Hypertriglyceridemia inPatients Receiving Retinoic Acid-Based Treatments

321 The Uses of RA-Based Medicines in Clinic RA-basedmedicines tretinoin (all-trans RA) isotretinoin (13-cis RA)and alitretinoin (9-cis RA) have been used in clinic to treatdiseases such as acute promyelocytic leukemia and skindisorders [11] In fact isotretinoin has been widely used totreat severe acne Early clinical observations indicate that themedical use of isotretinoin in human subjects results in theelevation of their plasma TG levels [195ndash197] A significantportion of patients with acne receiving isotretinoin treatmentdeveloped hypertriglyceridemia [9 10] In addition thesystemic administration of isotretinoin in patients with acneresulted in the elevation of plasma levels of alanine amino-transferase (ALT) and aspartate aminotransferase (AST)indicating the liver damage [198]The hypertriglyceridemia isalso associated with reduced insulin sensitivity and elevatedTG in the very-low-density lipoprotein (VLDL) fraction[195] The treatment of all-trans RA resulted in body massgain and hypertriglyceridemia in patients with acute promye-locytic leukemia [199 200] Moreover RA treatment alsoraises plasma TG levels in rats [201ndash203]

322 The Mechanism of RA-Mediated Hypertriglyceridemiain Patients Apo CIII is produced from liver and consideredan inhibitor of LPL activity [204] Mice with Apoc3 geneknockout have hypotriglyceridemia and enhanced in vivoVLDL-TG clearance [205] On the other hand transgenicmice with overexpression of apo CIII develop hypertriglyc-eridemia [206] The RA-induced hypertriglyceridemia hasbeen attributed to RA-induced apo CIII expression

In healthy human subjects isotretinoin treatment causesa rise of plasma apo CIII protein level [207]This is caused bythe induction of Apoc3 mRNA via the activation of RXR ata RARE in its promoter [207] The plasma TG levels in ratstreated with RXR-specific agonist (LG100268) are inducedrapidly and constantly [208] This results in the reducedactivity of LPL in the heart and skeletal muscle of thoseanimals [208] The RARE is identified in the C3P regionwhich controls the hepatic specific expression of Apoc3 gene[75] Interestingly the same site is also considered to beresponsible for mediating the effects of HNF4120572 and COUP-TFII onApoc3 gene expression [209]The expression ofApoc3seems to be regulated differently by the C3P-binding proteins[75]

It is worth to note that insulin suppresses Apoc3 mRNAexpression in STZ-induced diabetic mice [210] In additionthe activation of RXR by LG100268 treatment induces insulinsensitivity and reduces TG levels in obese and diabetic mice[211] The understanding of the regulatory mechanism thatintegrates hormonal and nutritional signals at the regulatorysites such as C3P in Apoc3 promoter will shed some lightson the regulation of hepatic lipid homeostasis It will also

10 ISRN Hepatology

provide a novel target for the treatment of the RA-inducedhypertriglyeridemia

323 The Effects of RA Treatment on Obesity Developmentin Mice Interestingly the RA administration in rodentscauses reduction of body mass as summarized in [212] Thiskind of reduction of body mass has been associated withenhancement of insulin sensitivity in genetic [213] or DIOmice [108] The mechanisms of RA-mediated attenuation ofinsulin resistance have been thought to be the induction ofenergy expenditure through PPAR120573120575 activation [108] andthe inhibition of adipogenesis throughRXR120574 activation [109]On the other hand retinol can be metabolized in adipose tis-sues [214]Themice with deletion ofRaldh1 gene (Raldh1minusminus)have elevated retinal in their adipose tissues and are resistantto diet-induced obesity and insulin resistance [26] This hasbeen attributed to the suppression of adipogenesis by retinal-inhibited activation of PPAR120574 and RXR [26] It is interestingto note that either retinal or RA can inhibit the adipogenesisand cause the improvement of insulin sensitivity in micebased on these studies

33 Roles of VA and Retinoids in the Regulation of HepaticLipogenic Gene Expression Insulin resistance diabetes andother metabolic abnormalities are associated with profoundchanges of hepatic lipid and glucose metabolismThis can beattributed at least in part to the altered expression of genesinvolved in glucose and lipid metabolism [215] The hepaticlipogenesis contributes to the homeostasis of FAs and TGs

331 The Regulation of Hepatic Srebp-1c Expression by VAStatus and Retinoids Treatment Insulin plays an essentialrole in the hepatic FA synthesis It has been known for a whilethat insulin is needed for the glucose usage for lipogenesis andCO2production in the liver [216] The hepatic FA synthesis

rises sharply and continuously after rats are fasted and thenrefed a high-carbohydrate diet [217] The amount of fattyacid synthase (FAS) is induced in normal rats refed a high-carbohydrate diet after fasting and in STZ-induced diabeticrats after insulin administration [218] In the insulin-deficientrats the induction of FAS after refeeding occurs only wheninsulin injection is injected [219] a process attributed to theinduction of FAS gene (Fas) [220 221]

The transcription of hepatic Fas is controlled by a tran-scription factor named SREBP-1c [222] In the liver-specificSrebp-1c knockoutmouse liver the induction of Fas and otherlipogenic genes by refeeding after fasting is blunted [223]Interestingly insulin also specifically induces the Srebp-1cexpression in the liver [224] via two liver X receptor elements(LXREs) and one sterol-responsive element (SRE) [225]However in liver-specific insulin receptor knockoutmice theinduction of hepatic Srebp-1c by refeeding largely remainedunchanged [226] This suggests that nutrient-derived signalsmay activate downstream of insulin receptor signaling path-way to regulate Srebp-1c expression and hepatic lipogenesis[226]

As stated in the previous section my research group hasobserved that the VAD ZL and ZF rats have lower plasma TG

levels than their VAS controls [116] This is accompanied bythe reduction of the hepatic expression of Srebp-1cmRNA inVA-deficient animals [116] My research group has reportedfor the first time that retinoids synergize with insulin toinduce the expression of Srebp-1c in primary rat hepatocytes[227] Further analysis of the Srebp-1c promoter reveals thatthe previous identified LXREs responsible for mediatinginsulin-induced Srebp-1c expression are also RAREs [227]These observations show that retinoids (nutritional) andinsulin (hormonal) signals converge to regulate the FAsynthesis in the liver

332 The Effects of VA Catabolism on the Regulation of Srebp-1c Expression in Primary Rat Hepatocytes More recentlyretinoids have been proposed to play roles in glucose and lipidmetabolism and to maintain energy homeostasis [228 229]VA (retinol) is reversibly converted into retinal and retinalis irreversibly converted into RA [23] Retinal the precursorof RA production is able to synergize with insulin to inducethe Srebp-1c expression in primary rat hepatocytes [227]This suggests that the dynamic production of RA influencesthe expression of hepatic lipogenic genes It has led us toinvestigate the roles of RA production in the insulin-resistantanimals

In the liver of the Raldh1minusminus mice RA production isreduced in response to a load of retinol [230] The Raldh1minusminusmice are resistant to the development of obesity and insulinresistance after being fed an HFD [26] This is attributed tothe elevation of retinal content due to the lack of conversionof retinal to RA in the adipose tissues of the Raldh1minusminusmice Additionally the liver of the Raldh1minusminus mice hasaltered regulation of the genes for gluconeogenesis andsignificantly attenuated hepatic TG synthesis indicating theimportant role of hepatic VAmetabolism in glucose and lipidhomeostasis [231]

The hepatic expression levels of RALDH1 and RALDH2are induced in mice fed a high-cholesterol diet [232] SREsare located in the promoters of these two genes whichare induced by SREBP-1c overexpression The expression ofSrebp-1c is induced by the oxysterols derived from the high-cholesterol diet [232] This research work demonstrates theinteraction of cholesterol and RA metabolism in the liver Inaddition it has been shown that the level of Raldh1mRNA iselevated in the kidney of dbdb mice [233] Both dbdb miceand ZF rats develop obesity due to the mutation of leptinreceptor [234]

In an attempt to understand the roles of VA metabolismin the states of metabolic diseases we have compared theexpression levels of enzymes responsible for the productionof retinal and RA in the freshly isolated and cultured primaryhepatocytes from ZL rats and ZF rats [45] We have foundthat in the primary rat hepatocytes the enzymes responsiblefor the conversions of retinol to retinal and from retinal toRA are most likely RDH2 and RALDH1 respectively Theexpression levels of Raldh1 mRNA and its protein are higherin hepatocytes from ZF rats than in those from ZL rats[45] When overexpressed RALDH1 introduces the retinal-mediated induction of Srebp-1c in INS-1 cells which do not

ISRN Hepatology 11

respond to retinal in our previous study [227] These resultsindicate that insulin-resistant animals such as ZF rats mayhave alterations in retinoids metabolism

Thus we have hypothesized that the change of RAproduction from the oversupply of dietary VA due to thehyperphagia of ZF rats results in higher Srebp-1c expressionin ZF hepatocytes [45] The elevated SREBP-1c expressioncan further induceRaldh1 expression to create a feed-forwardmechanism that could be one of the reasons responsible forthe increased lipogenesis in the liver of ZF rats All of theseobservations indicate the potential roles of RA metabolismin the development of obesity and insulin resistance whichdeserves to be further studied

4 VArsquos Roles in Mediating Hepatic InsulinAction and Insulin Resistance

41 Insulin and Its Signal Transduction The insulin moleculeis made of two chains linked by one intra- and one interchaindisulfide bonds [235] The insulin receptor is a transmem-brane and heterotetramer tyrosine kinase receptor (two 120572and two 120573 subunits) linked by disulfide bonds as well [236]The binding of insulin to its receptor causes conformationchanges and transphosphorylation of the 120573-subunit tyrosinekinase [237 238] which initiates the signal transduction[239] Protein-protein interactions are involved in the trans-duction of insulin signalThe signal is transduced bymultiplecomponents in a complex network containing cascades ofkinases and phosphatases [240 241] The first intracellularcomponents mediating insulin signals are insulin recep-tor substrates (IRSs) protein molecules phosphorylated byinsulin receptor 120573-subunit and mediating insulin signals[242]

The insulin signal event is further amplified byphosphatidylinositide 3-kinases (PI3K)protein kinaseB (PKBAkt) pathway and GRB2mitogen-activated proteinkinase (MAPK) pathway [243ndash245] Another serinethre-onine kinase that can be activated by PI3K is the atypicalprotein kinase C [246] Human liver expresses severalprotein-tyrosine phosphatases (PTPs) [247] Okadai acid aninhibitor of protein phosphatase type 2A and type 1 inhibitsglycogen synthesis and insulin-stimulated Gck expression inprimary rat hepatocytes indicating that dephosphorylationmechanism may also participate in mediating insulinsignaling [248] These components are shared by insulin-likegrowth factor (IGF) receptor and involved in mediatinginsulin and IGF signals [249]

42 Metabolic Diseases and Insulin Resistance The rise ofthe number of people with one or more metabolic diseasessuch as obesity and diabetes in the world has become apublic health problem [250] The interactions of genetic andenvironmentalnutritional factors may be responsible for thecurrent rise of metabolic diseases The long evolutionaryprocess has equipped human and animal bodieswith a varietyof regulatory mechanisms controlling these interactions [251252] Human diets contain not only energy derived frommacronutrients but also micronutrients and other factors

which may influence the metabolic outcomes The roles ofindividual micronutrients in the development of metabolicdiseases are still unrevealed

One common property of human obesity and NIDDMis insulin resistance in which a given amount of insulinproduces less than normal physiological responses Dietaryfactors and manipulations have been considered to play arole in the development of insulin resistance in humans andanimals For example feeding an HFD to young and insulin-sensitive subjects for two days causes the development ofglucose intolerance [253] In the skeletal muscle of rats fedan HFD for 8 weeks the insulin-induced glucose uptakeis impaired [254] FFAs have been considered the factorsresponsible for HFD-induced leptin and insulin resistance[255ndash257]

43 Hepatic Insulin Resistance and Vicious Cycle The liverplays an essential role in the control of glucose andlipid homeostasis It coordinately regulates the processesin responses to nutritional and hormonal stimuli Insulinplays a major role in directing the liverrsquos metabolic status[258] which is partially attributed to the regulation of theexpression of genes involved in hepatic glucose and lipidmetabolism [215 259]

Insulin controls the expression of a variety of genesinvolved in glycolysis glycogenesis and lipogenesis andgluconeogenesis in the liver [145] Generally hepatic lipidand glucose metabolism is altered with the development ofinsulin resistance in obesity and NIDDM [258] This canbe reflected in the expression of insulin-regulated hepaticgenes for glucose and FA metabolism When the liver isinsulin sensitive insulin stimulates lipogenesis and inhibitsgluconeogenesis For example to regulate hepatic glucosehomeostasis insulin increases the expression of Gck gene[119 120] and Srebp-1c [224] a family member of SREBPswhich regulate the hepatic cholesterol and FA biosynthesisand their homeostasis [260] It suppresses the expressionof Pck1 [142] and G6pc [145] which control the first andlast steps of gluconeogenesis respectively When the liver isinsulin resistant insulin no longer inhibits gluconeogenesisHowever the liver still keeps the elevated lipogenesis Theelevated FA biosynthesis in the insulin-resistant state furtherfacilitates insulin secretion from pancreatic 120573-cells whichprobably enhances lipogenesis and results in a vicious cycle[113 261] The coexistence of the hepatic insulin resistanceand sensitivity at the gene expression level has been observedin rodent obese and diabetic models [215 258] Howeverthe mechanism of this coexistence of insulin sensitivity andresistance has not been revealed [261]

Recently the SREBP cleavage-activating protein gene(Scap) an escort protein necessary for generating nuclearforms of SREBPs has been knocked out in insulin-resistantobob mice [262] Deficiency of hepatic Scap reverses liverlipogenesis and steatosis in obobmice However the plasmalevels of glucose and insulin and the hepatic expression levelsof Pck1 andG6pcwere not different between the control obobmice and the obob mice with liver-specific Scap knockout[262] It seems that the suppression of hepatic FA synthesis

12 ISRN Hepatology

is not sufficient to correct insulin resistance Whether otherfactors play a role in the hepatic insulin resistance is still anopen question

The clinical use of RA-based medicine such asisotretinoin (13-cis RA) caused elevation of plasma TGlevels in human subjects [195ndash197] This increase in plasmaTG levels is also observed in rats [201ndash203] From our VAstatus studies we have shown that VA status affected theobesity development in ZF rats and reduced plasma insulinand TG levels in ZL and ZF rats suggesting improvement ofinsulin sensitivity [116] The hepatic expression of Srebp-1cwas reduced in VA-deficient animals [116] RA synergizeswith insulin to induce the expression of Srebp-1c in primaryrat hepatocytes [227] On the other hand RA treatmentinduces Pck1 expression and attenuates insulin-mediatedsuppression of its expression in primary rat hepatocytes [172]All of these observations demonstrate that RA attenuatesinsulin action (insulin-suppressed Pck1 expression) andstill promotes insulin action (insulin-induced Srebp-1cexpression) in the same primary hepatocytes

44 Possible Mechanism by Which RA Production Causes theDevelopment of the Vicious Cycle in Hepatocytes Could RAor other metabolites from VA catabolism be a factor thatcontributes to the hepatic insulin resistance and the viciouscycleUsing the regulation ofPck1 and Srebp-1c as themodel Ihave come upwith the following scheme to show that retinoidmetabolism could be a factor that causes the vicious cycle inthe liver As shown in Figure 3(a) in insulin-sensitive hepa-tocytes RA derived from retinal coordinates with insulin toregulate the expression of Srebp-1c and Pck1 The SREBP-1cprotein is processed to mature form a step that can be facili-tated by insulin [263] The mature form of SREBP-1c entersinto the nucleus and induces the mRNA levels of Raldh1and Fas which are respectively transcribed into RALDH1and FAS RALDH1 catalyzes the conversion of retinal to RAFAS catalyzes the synthesis of palmitate which is esterifiedinto TGs or elongated to longer FAs The Pck1 mRNA isused to translate into PEPCK-C protein which contributesto glucogenogenesis In the insulin-resistant hepatocytes asshown in Figure 3(b) the elevation of Raldh1 expressiondue to leptin deficiency [45] or induction of SREBP-1c byhigh-cholesterol feeding [232] induces the production of RAThe elevated RA levels will stimulate the transcription ofSrebp-1c and Pck1 This leads to more production of SREBP-1c and its mature form in the presence of higher insulinlevels in the insulin-resistant state The induction of SREBP-1c further enhances the transcription of Raldh1 and Fas andtheir corresponding proteins for the production of moreRAs and FAs respectively The RA production and SREBP-1c expression form a feed-forward cycle which causes moreTG and RA production in the insulin-resistant liver At thesame time more of the PEPCK-C protein is generated dueto the elevated Pck1 transcription by RA stimulation whichis not responsive to insulin inhibition as we have shown in[172] This leads to elevated gluconeogenesis in the insulin-resistant liver Eventually the phenotypes appear as if insulin

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1cRetinal

RALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(a) Insulin-sensitive hepatocytes

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1c

RetinalRALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(b) Insulin-resistant hepatocytes

Figure 3 The effects of RA on the insulin-regulated Srebp-1cand Pck1 expression levels the protein levels of SREBP-1c theexpression levels of Raldh1 and Fas and the fatty acid synthesisand gluconeogenesis in insulin-sensitive (a) and insulin-resistant (b)hepatocytes Please see the text in this paper for description Uparrows next to the text indicate induction The intensified weight ofthe lines indicates the induction of that part of the pathway

no longer suppresses gluconeogenesis while it still stimulatesFA synthesis in the insulin-resistant state

5 Perspectives and Future Directions

I have proposed a mechanism by which VA metabolismcontributes to the development of hepatic insulin resistanceIt explains some observations reported in the previous studiesof rodent obese and diabetic models [215 258] However itleavesmore open questionsThefirst one iswhat the initiationfactor is So far the elevated expression of Raldh1 mRNA inthe liver has been observed in ZF rats [45] and mice fed ahigh-cholesterol diet [232] These two conditions cause a lotof physiological changes such as overfeeding in ZF rats andchange of cholesterol biosynthesis in response to the feedingof high-cholesterol diet Knocking down Raldh1 specificallyin hepatocytes is needed to answer these questions The

ISRN Hepatology 13

second question is whether RA synthesis in hepatocytesis a regulated process in response to dietary or hormonalstimulations If Raldh1 is a downstream gene of SREBP-1cit should be regulated when the SREBP-1c level changes Asthe expression of Srebp-1c responds to insulin stimulation andoxysterols the regulation of Raldh1 expression in the livershould be studied The third question is why it is RALDH1but not other RALDHs Specific inhibitors of RALDHsmay be needed to answer this question Last question iswhether we can attenuate insulin resistance by suppressingthe RALDH1 activity in the liver It has been shown thatRaldh1minusminus mice are still insulin sensitive when they are onan HFD [26] This has been attributed to the effects on theadipogenesis However the liver of those knockout mice hasreduced lipid synthesis [231] Further studies are warrantedto answer all of these questions Hopefully it can become anintervention point for the treatment of insulin resistance andmetabolic diseases

Acknowledgments

This work was financially supported by a research grantfrom Allen Foundation Inc (to Guoxun Chen) a start-up fund from the University of Tennessee at Knoxville (toGuoxun Chen) and a Scientist Development Grant fromthe AmericanHeart Association (09SDG2140003 to GuoxunChen) The author thanks his colleague Dr Lauren Gellar forreading through this paper and offering her edits

References

[1] F G Hopkins ldquoFeeding experiments illustrating the impor-tance of accessory factors in normal dietariesrdquo The Journal ofPhysiology vol 44 no 5-6 pp 425ndash460 1912

[2] K J Carpenter ldquoA short history of nutritional science part 3(1912ndash1944)rdquo Journal of Nutrition vol 133 no 10 pp 3023ndash30322003

[3] E V McCollum and M Davis ldquoThe necessity of certain lipinsin the diet during growthrdquo Journal of Biological Chemistry vol15 no 1 pp 167ndash175 1913

[4] T B Osborne and L B Mendel ldquoFeeding experiments with fat-free food mixturesrdquo Journal of Biological Chemistry vol 12 no1 pp 81ndash89 1912

[5] R D Semba ldquoOn the lsquoDiscoveryrsquo of Vitamin Ardquo Annals ofNutrition and Metabolism vol 61 no 3 pp 192ndash198 2012

[6] R Blomhoff and H K Blomhoff ldquoOverview of retinoidmetabolism and functionrdquo Journal of Neurobiology vol 66 no7 pp 606ndash630 2006

[7] A Sommer ldquoVitamin A deficiency and clinical disease anhistorical overviewrdquo Journal of Nutrition vol 138 no 10 pp1835ndash1839 2008

[8] K J Rothman L L Moore M R Singer U-S Nguyen SMannino and A Milunsky ldquoTeratogenicity of high vitamin Aintakerdquo The New England Journal of Medicine vol 333 no 21pp 1369ndash1373 1995

[9] S Bershad A Rubinstein and J R Paterniti Jr ldquoChanges inplasma lipids and lipoproteins during isotretinoin therapy foracnerdquoThe New England Journal of Medicine vol 313 no 16 pp981ndash985 1985

[10] N Rodondi R Darioli A-A Ramelet et al ldquoHigh risk forhyperlipidemia and the metabolic syndrome after an episodeof hypertriglyceridemia during 13-cis retinoic acid therapy foracne a pharmacogenetic studyrdquo Annals of Internal Medicinevol 136 no 8 pp 582ndash589 2002

[11] H-U Klor A Weizel M Augustin et al ldquoThe impact oforal vitamin A derivatives on lipid metabolism what recom-mendations can be derived for dealing with this issue in thedaily dermatological practicerdquo Journal of the German Societyof Dermatology vol 9 no 8 pp 600ndash607 2011

[12] R M Russell ldquoThe vitamin A spectrum from deficiency totoxicityrdquoThe American Journal of Clinical Nutrition vol 71 no4 pp 878ndash884 2000

[13] A C Ross B Caballero R J Cousins K L Tucker and T RZiegler Modern Nutrition in Health and Diseases 11th edition2012

[14] E H Harrison ldquoMechanisms of digestion and absorption ofdietary vitamin Ardquo Annual Review of Nutrition vol 25 no 1pp 87ndash103 2005

[15] M R Lakshman ldquoAlpha and omega of carotenoid cleavagerdquoJournal of Nutrition vol 134 no 1 pp 241ndash245 2004

[16] I Potrykus ldquoNutritionally enhanced rice to combat malnutri-tion disorders of the poorrdquo Nutrition Reviews vol 61 no 6 ppS101ndashS104 2003

[17] A Wyss ldquoCarotene oxygenases a new family of double bondcleavage enzymesrdquo Journal of Nutrition vol 134 no 1 pp 246ndash250 2004

[18] R Kawaguchi J Yu J Honda et al ldquoA membrane receptor forretinol binding protein mediates cellular uptake of vitamin ArdquoScience vol 315 no 5813 pp 820ndash825 2007

[19] P Alapatt F Guo S M Komanetsky et al ldquoLiver retinoltransporter and receptor for serum retinol-binding protein(RBP4)rdquo Journal of Biological Chemistry vol 288 no 2 pp1250ndash1265 2013

[20] A R Moise N Noy K Palczewski and W S Blaner ldquoDeliveryof retinoid-based therapies to target tissuesrdquo Biochemistry vol46 no 15 pp 4449ndash4458 2007

[21] G Duester ldquoFamilies of retinoid dehydrogenases regulatingvitamin A function Production of visual pigment and retinoicacidrdquo European Journal of Biochemistry vol 267 no 14 pp4315ndash4324 2000

[22] M Theodosiou V Laudet and M Schubert ldquoFrom carrotto clinic an overview of the retinoic acid signaling pathwayrdquoCellular andMolecular Life Sciences vol 67 no 9 pp 1423ndash14452010

[23] J L Napoli ldquoInteractions of retinoid binding proteins andenzymes in retinoidmetabolismrdquoBiochimica et BiophysicaActavol 1440 no 2-3 pp 139ndash162 1999

[24] X Chai M H E M Boerman Y Zhai and J L NapolildquoCloning of a cDNA for liver microsomal retinol dehydro-genase A tissue-specific short-chain alcohol dehydrogenaserdquoJournal of Biological Chemistry vol 270 no 8 pp 3900ndash39041995

[25] B X Wu G Moiseyev Y Chen B Rohrer R K Crouch andJ-XMa ldquoIdentification of RDH10 an all-trans retinol dehydro-genase in retinal Muller cellsrdquo Investigative Ophthalmology andVisual Science vol 45 no 11 pp 3857ndash3862 2004

[26] O Ziouzenkova G Orasanu M Sharlach et al ldquoRetinalde-hyde represses adipogenesis and diet-induced obesityrdquo NatureMedicine vol 13 no 6 pp 695ndash702 2007

14 ISRN Hepatology

[27] J L Napoli ldquoPhysiological insights into all-trans-retinoic acidbiosynthesisrdquo Biochimica et Biophysica Acta vol 1821 no 1 pp152ndash167 2012

[28] G Wolf ldquoTissue-specific increases in endogenous all-transretinoic acid possible contributing factor in ethanol toxicityrdquoNutrition Reviews vol 68 no 11 pp 689ndash692 2010

[29] P V Bhat J Labrecque JM Boutin A Lacroix andA YoshidaldquoCloning of a cDNA encoding rat aldehyde dehydrogenase withhigh activity for retinal oxidationrdquoGene vol 166 no 2 pp 303ndash306 1995

[30] M Lin M Zhang M Abraham S M Smith and J LNapoli ldquoMouse retinal dehydrogenase 4 (RALDH4) molecularcloning cellular expression and activity in 9-cis-retinoic acidbiosynthesis in intact cellsrdquo Journal of Biological Chemistry vol278 no 11 pp 9856ndash9861 2003

[31] F A Mic A Molotkov X Fan A E Cuenca and GDuester ldquoRALDH3 a retinaldehyde dehydrogenase that gener-ates retinoic acid is expressed in the ventral retina otic vesicleand olfactory pit during mouse developmentrdquo Mechanisms ofDevelopment vol 97 no 1-2 pp 227ndash230 2000

[32] X Wang P Penzes and J L Napoli ldquoCloning of a cDNAencoding an aldehyde dehydrogenase and its expression inEscherichia coli recognition of retinal as substraterdquo Journal ofBiological Chemistry vol 271 no 27 pp 16288ndash16293 1996

[33] A Molotkov and G Duester ldquoGenetic evidence that retinalde-hyde dehydrogenase Raldh1 (Aldh1a1) functions downstreamof alcohol dehydrogenase Adh1 in metabolism of retinol toretinoic acidrdquo Journal of Biological Chemistry vol 278 no 38pp 36085ndash36090 2003

[34] G Elizondo J Corchero E Sterneck and F J GonzalezldquoFeedback inhibition of the retinaldehyde dehydrogenase geneALDH1 by retinoic acid through retinoic acid receptor 120572and CCAATenhancer-binding protein 120573rdquo Journal of BiologicalChemistry vol 275 no 50 pp 39747ndash39753 2000

[35] G Elizondo I M Medina-Dıaz R Cruz F J Gonzalez and LVega ldquoRetinoic acid modulates retinaldehyde dehydrogenase 1gene expression through the induction of GADD153-CEBP120573interactionrdquo Biochemical Pharmacology vol 77 no 2 pp 248ndash257 2009

[36] K Fujiwara M Kikuchi K Horiguchi et al ldquoEstrogen receptoralpha regulates retinaldehyde dehydrogenase 1 expression in ratanterior pituitary cellsrdquo Endocrine Journal vol 56 no 8 pp963ndash973 2009

[37] K Fujiwara F Maekawa M Kikuchi S Takigami T Yadaand T Yashiro ldquoExpression of retinaldehyde dehydrogenase(RALDH)2 and RALDH3 but not RALDH1 in the developinganterior pituitary glands of ratsrdquo Cell and Tissue Research vol328 no 1 pp 129ndash135 2007

[38] GWolf ldquoThe enzymatic cleavage of 120573-carotene still controver-sialrdquo Nutrition Reviews vol 53 no 5 pp 134ndash137 1995

[39] S Abu-Abed P Dolle D Metzger B Beckett P Chambonand M Petkovich ldquoThe retinoic acid-metabolizing enzymeCYP26A1 is essential for normal hindbrain patterning verte-bral identity and development of posterior structuresrdquo Genesand Development vol 15 no 2 pp 226ndash240 2001

[40] M A Leo S Iida and C S Lieber ldquoRetinoic acid metabolismby a system reconstituted with cytochrome P-450rdquo Archives ofBiochemistry and Biophysics vol 234 no 1 pp 305ndash312 1984

[41] MA Leo JM Lasker J L Raucy C-I KimM Black andC SLieber ldquoMetabolism of retinol and retinoic acid by human livercytochrome P450IIC8rdquoArchives of Biochemistry and Biophysicsvol 269 no 1 pp 305ndash312 1989

[42] R Quere A Baudet B Cassinat et al ldquoPharmacogenomicanalysis of acute promyelocytic leukemia cells highlightsCYP26cytochrome metabolism in differential all-trans retinoic acidsensitivityrdquo Blood vol 109 no 10 pp 4450ndash4460 2007

[43] J AWhite B Beckett-Jones Y-D Guo et al ldquocDNA cloning ofhuman retinoic acid-metabolizing enzyme (hP450RAI) identi-fies a novel family of cytochromes p450 (CYP26)rdquo Journal ofBiological Chemistry vol 272 no 30 pp 18538ndash18541 1997

[44] Y Zhang R Zolfaghari Reza and A C Ross ldquoMultiple retinoicacid response elements cooperate to enhance the inducibility ofCYP26A1 gene expression in liverrdquo Gene vol 464 no 1-2 pp32ndash43 2010

[45] Y Li Y Zhang R Li et al ldquoThe hepatic raldh1 expression iselevated in Zucker fatty rats and its over-expression introducedthe retinal-induced Srebp-1c expression in INS-1 cellsrdquo PLoSONE vol 7 no 9 Article ID e45210 2012

[46] R M Evans ldquoThe nuclear receptor superfamily a Rosetta stonefor physiologyrdquo Molecular Endocrinology vol 19 no 6 pp1429ndash1438 2005

[47] P Chambon ldquoA decade of molecular biology of retinoic acidreceptorsrdquo FASEB Journal vol 10 no 9 pp 940ndash954 1996

[48] D J Mangelsdorf and RM Evans ldquoThe RXR heterodimers andorphan receptorsrdquo Cell vol 83 no 6 pp 841ndash850 1995

[49] J E Balmer and R Blomhoff ldquoA robust characterization ofretinoic acid response elements based on a comparison of sitesin three speciesrdquo Journal of Steroid Biochemistry and MolecularBiology vol 96 no 5 pp 347ndash354 2005

[50] R Kurokawa J DiRenzo M Boehm et al ldquoRegulation ofretinoid signalling by receptor polarity and allosteric control ofligand bindingrdquo Nature vol 371 no 6497 pp 528ndash531 1994

[51] A Cvekl and W-L Wang ldquoRetinoic acid signaling in mam-malian eye developmentrdquo Experimental Eye Research vol 89no 3 pp 280ndash291 2009

[52] V Dupe M Davenne J Brocard et al ldquoIn vivo functional anal-ysis of the Hoxa-1 31015840 retinoic acid response element (31015840RARE)rdquoDevelopment vol 124 no 2 pp 399ndash410 1997

[53] A C Ross ldquoRetinoid production and catabolism role of dietin regulating retinol esterification and retinoic acid oxidationrdquoJournal of Nutrition vol 133 no 1 pp 291ndash296 2003

[54] T Moore and P D Holmes ldquoThe production of experimentalvitamin A deficiency in rats andmicerdquo Laboratory Animals vol5 no 2 pp 239ndash250 1971

[55] A C Ross and E H Harrison ldquoVitamin A and carotenoidsrdquoin Handbook of Vitamins D E McCormick R R Rucker J WSuttie et al Eds CRC Press Boca Raton Fla USA 4th edition2006

[56] A Chawta J J Repa R M Evans and D J MangelsdorfldquoNuclear receptors and lipid physiology opening the x-filesrdquoScience vol 294 no 5548 pp 1866ndash1870 2001

[57] C K Glass and M G Rosenfeld ldquoThe coregulator exchangein transcriptional functions of nuclear receptorsrdquo Genes andDevelopment vol 14 no 2 pp 121ndash141 2000

[58] A L Bookout Y Jeong M Downes R T Yu R M EvansandD JMangelsdorf ldquoAnatomical profiling of nuclear receptorexpression reveals a hierarchical transcriptional networkrdquo Cellvol 126 no 4 pp 789ndash799 2006

[59] B Mascrez M Mark W Krezel et al ldquoDifferential contribu-tions of AF-1 andAF-2 activities to the developmental functionsof RXR120572rdquo Development vol 128 no 11 pp 2049ndash2062 2001

[60] D Li T Li F Wang H Tian and H H Samuels ldquoFunctionalevidence for retinoid X receptor (RXR) as a nonsilent partner

ISRN Hepatology 15

in the thyroid hormone receptorRXR heterodimerrdquoMolecularand Cellular Biology vol 22 no 16 pp 5782ndash5792 2002

[61] F M Sladek W Zhong E Lai and J E Darnell Jr ldquoLiver-enriched transcription factor HNF-4 is a novel member ofthe steroid hormone receptor superfamilyrdquo Genes and Develop-ment vol 4 no 12 pp 2353ndash2365 1990

[62] K Yamagata H Furuta N Oda et al ldquoMutations in thehepatocyte nuclear factor-4120572 gene inmaturity-onset diabetes ofthe young (MODY1)rdquo Nature vol 384 no 6608 pp 458ndash4601996

[63] M Stoffel and S ADuncan ldquoThematurity-onset diabetes of theyoung (MODY1) transcription factor HNF4120572 regulates expres-sion of genes required for glucose transport and metabolismrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 24 pp 13209ndash13214 1997

[64] M Lehto P-O Bitzen B Isomaa et al ldquoMutation in the HNF-4120572 gene affects insulin secretion and triglyceride metabolismrdquoDiabetes vol 48 no 2 pp 423ndash425 1999

[65] G P Hayhurst Y-H Lee G Lambert J M Ward and F JGonzalez ldquoHepatocyte nuclear factor 4120572 (Nuclear receptor 2A1)is essential formaintenance of hepatic gene expression and lipidhomeostasisrdquo Molecular and Cellular Biology vol 21 no 4 pp1393ndash1403 2001

[66] U Roth K Jungermann and T Kietzmann ldquoActivation ofglucokinase gene expression by hepatic nuclear factor 4120572 inprimary hepatocytesrdquo Biochemical Journal vol 365 no 1 pp223ndash228 2002

[67] S Mandard R Stienstra P Escher et al ldquoGlycogen synthase2 is a novel target gene of peroxisome proliferator-activatedreceptorsrdquo Cellular and Molecular Life Sciences vol 64 no 9pp 1145ndash1157 2007

[68] F Rajas A Gautier I Bady S Montano and G MithieuxldquoPolyunsaturated fatty acyl coenzyme a suppress the glucose-6-phosphatase promoter activity bymodulating the DNA bindingof hepatocyte nuclear factor 4120572rdquo Journal of Biological Chemistryvol 277 no 18 pp 15736ndash15744 2002

[69] B Viollet A Kahn and M Raymondjean ldquoProtein kinase A-dependent phosphorylation modulates DNA-binding activityof hepatocyte nuclear factor 4rdquoMolecular and Cellular Biologyvol 17 no 8 pp 4208ndash4219 1997

[70] L Palanker J M Tennessen G Lam and C S Thum-mel ldquoDrosophila HNF4 regulates lipid mobilization and 120573-oxidationrdquo Cell Metabolism vol 9 no 3 pp 228ndash239 2009

[71] A Miura K Yamagata M Kakei et al ldquoHepatocyte nuclearfactor-4120572 is essential for glucose-stimulated insulin secretion bypancreatic 120573-cellsrdquo Journal of Biological Chemistry vol 281 no8 pp 5246ndash5257 2006

[72] R Bartoov-Shifman R Hertz H Wang C B Wollheim JBar-Tana and M D Walker ldquoActivation of the insulin genepromoter through a direct effect of hepatocyte nuclear factor4120572rdquo Journal of Biological Chemistry vol 277 no 29 pp 25914ndash25919 2002

[73] H Wang P Maechler P A Antinozzi K A Hagenfeldt andC B Wollheim ldquoHepatocyte nuclear factor 4120572 regulates theexpression of pancreatic 120573-cell genes implicated in glucosemetabolism and nutrient-induced insulin secretionrdquo Journal ofBiological Chemistry vol 275 no 46 pp 35953ndash35959 2000

[74] K Reue T Leff and J L Breslow ldquoHuman apolipoproteinCIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factorsrdquo Journal ofBiological Chemistry vol 263 no 14 pp 6857ndash6864 1988

[75] T Leff K Reue A Melian H Culver and J L BreslowldquoA regulatory element in the apoCIII promoter that directshepatic specific transcription binds to proteins in expressingand nonexpressing cell typesrdquo Journal of Biological Chemistryvol 264 no 27 pp 16132ndash16137 1989

[76] S N Lavrentiadou M Hadzopoulou-Cladaras D Kardassisand V I Zannis ldquoBinding specificity and modulation of thehuman apocIII promoter activity by heterodimers of ligand-dependent nuclear receptorsrdquo Biochemistry vol 38 no 3 pp964ndash975 1999

[77] T R Magee Y Cai M E El-Houseini J Locker and Y-JY Wan ldquoRetinoic acid mediates down-regulation of the 120572-fetoprotein gene through decreased expression of hepatocytenuclear factorsrdquo Journal of Biological Chemistry vol 273 no 45pp 30024ndash30032 1998

[78] A Qian Y Cai T R Magee and Y J Y Wan ldquoIdentificationof retinoic acid-responsive elements on the HNF1alpha andHNF4alpha genesrdquo Biochemical and Biophysical Research Com-munications vol 276 no 3 pp 837ndash842 2000

[79] H Nakshatri and P Chambon ldquoThe directly repeatedRG(GT)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites forRAR RXR HNF-4 and ARP-1 homo- and heterodimersrdquoJournal of Biological Chemistry vol 269 no 2 pp 890ndash9021994

[80] T Makita G Hernandez-Hoyos T H-P Chen H Wu E VRothenberg and H M Sucov ldquoA developmental transition indefinitive erythropoiesis erythropoietin expression is sequen-tially regulated by retinoic acid receptors andHNF4rdquoGenes andDevelopment vol 15 no 7 pp 889ndash901 2001

[81] T I Kambe J Tada-Kambe Y Kuge Y Yamaguchi-Iwai MNagao and R Sasaki ldquoRetinoic acid stimulates erythropoietingene transcription in embryonal carcinoma cells through thedirect repeat of a steroidthyroid hormone receptor responseelement half-site in the hypoxia-response enhancerrdquo Blood vol96 no 9 pp 3265ndash3271 2000

[82] F-J Lin J Qin K Tang S Y Tsai and M-J Tsai ldquoCoup drsquoEtatan orphan takes controlrdquo Endocrine Reviews vol 32 no 3 pp404ndash421 2011

[83] L-H Wang S Y Tsai R G Cook W G Beattie M-J Tsaiand BW OrsquoMalley ldquoCOUP transcription factor is a member ofthe steroid receptor superfamilyrdquoNature vol 340 no 6229 pp163ndash166 1989

[84] X Leng A J Cooney S Y Tsai and M-J Tsai ldquoMolecularmechanisms of COUP-TF-mediated transcriptional repressionevidence for transrepression and active repressionrdquo Molecularand Cellular Biology vol 16 no 5 pp 2332ndash2340 1996

[85] L Li X Xie J Qin et al ldquoThe nuclear orphan receptorCOUP-TFII plays an essential role in adipogenesis glucosehomeostasis and energy metabolismrdquo Cell Metabolism vol 9no 1 pp 77ndash87 2009

[86] F A Pereira Q Yuhong G Zhou M-J Tsai and S YTsai ldquoThe orphan nuclear receptor COUP-TFII is required forangiogenesis and heart developmentrdquo Genes and Developmentvol 13 no 8 pp 1037ndash1049 1999

[87] N Takamoto I Kurihara K Lee F J DeMayo M-J Tsai andS Y Tsai ldquoHaploinsufficiency of chicken ovalbumin upstreampromoter transcription factor II in female reproductionrdquoMolec-ular Endocrinology vol 19 no 9 pp 2299ndash2308 2005

[88] P Zhang M Bennoun C Gogard et al ldquoExpression of COUP-TFII in metabolic tissues during developmentrdquo Mechanisms ofDevelopment vol 119 no 1 pp 109ndash114 2002

16 ISRN Hepatology

[89] Z Xu S Yu C-H Hsu J Eguchi and E D Rosen ldquoTheorphan nuclear receptor chicken ovalbumin upstream pro-moter-transcription factor II is a critical regulator of adipogene-sisrdquoProceedings of theNationalAcademy of Sciences of theUnitedStates of America vol 105 no 7 pp 2421ndash2426 2008

[90] P Bardoux P Zhang D Flamez et al ldquoEssential role of chickenovalbumin upstreampromoter-transcription factor II in insulinsecretion and insulin sensitivity revealed by conditional geneknockoutrdquo Diabetes vol 54 no 5 pp 1357ndash1363 2005

[91] G Achatz B Holzl R Speckmayer C Hauser F Sandhoferand B Paulweber ldquoFunctional domains of the human orphanreceptor ARP-1COUP-TFII involved in active repression andtransrepressionrdquo Molecular and Cellular Biology vol 17 no 9pp 4914ndash4932 1997

[92] S A Kliewer K Umesono R A Heyman D J MangelsdorfJ A Dyck and R M Evans ldquoRetinoid X receptor-COUP-TFinteractionsmodulate retinoic acid signalingrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol89 no 4 pp 1448ndash1452 1992

[93] A J Cooney S Y Tsai BW OrsquoMalley andM-J Tsai ldquoChickenovalbumin upstreampromoter transcription factor (COUP-TF)dimers bind to different GGTCA response elements allowingCOUP-TF to repress hormonal induction of the vitamin D3thyroid hormone and retinoic acid receptorsrdquo Molecular andCellular Biology vol 12 no 9 pp 4153ndash4163 1992

[94] SW Kruse K Suino-Powell X E Zhou et al ldquoIdentification ofCOUP-TFII orphannuclear receptor as a retinoic acid-activatedreceptorrdquo PLoS Biology vol 6 no 9 Article ID e227 2008

[95] J P Berger T E Akiyama and P T Meinke ldquoPPARs thera-peutic targets for metabolic diseaserdquo Trends in PharmacologicalSciences vol 26 no 5 pp 244ndash251 2005

[96] JM Peters andF J Gonzalez ldquoSorting out the functional role(s)of peroxisome proliferator-activated receptor-120573120575 (PPAR120573120575)in cell proliferation and cancerrdquo Biochimica et Biophysica Actavol 1796 no 2 pp 230ndash241 2009

[97] A Tenenbaum and E Fisman ldquoBalanced pan-PPAR activatorbezafibrate in combination with statin comprehensive lipidscontrol and diabetes preventionrdquo Cardiovascular Diabetologyvol 11 no 1 article 140 2012

[98] O Braissant F Foufelle C Scotto M Dauca and W WahlildquoDifferential expression of peroxisome proliferator-activatedreceptors (PPARs) tissue distribution of PPAR-120572 -120573 and -120574 inthe adult ratrdquo Endocrinology vol 137 no 1 pp 354ndash366 1996

[99] H Higashiyama A N Billin Y Okamoto M Kinoshita andS Asano ldquoExpression profiling of Peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues usingtissue microarrayrdquo Histochemistry and Cell Biology vol 127 no5 pp 485ndash494 2007

[100] P S Jones R Savory P Barratt et al ldquoChromosomal local-isation inducibility tissue-specific expression and strain dif-ferences in three murine peroxisome-proliferator-activated-receptor genesrdquo European Journal of Biochemistry vol 233 no1 pp 219ndash226 1995

[101] S A Kliewer B M Forman B Blumberg et al ldquoDifferentialexpression and activation of a family of murine peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no15 pp 7355ndash7359 1994

[102] E E Girroir H E Hollingshead P He B Zhu G H Perdewand J M Peters ldquoQuantitative expression patterns of peroxi-some proliferator-activated receptor-120573120575 (PPAR120573120575) protein in

micerdquo Biochemical and Biophysical Research Communicationsvol 371 no 3 pp 456ndash461 2008

[103] P Escher O Braissant S Basu-Modak L Michalik W Wahliand B Desvergne ldquoRat PPARs quantitative analysis in adult rattissues and regulation in fasting and refeedingrdquo Endocrinologyvol 142 no 10 pp 4195ndash4202 2001

[104] D Auboeuf J Rieusset L Fajas et al ldquoTissue distributionand quantification of the expression of mRNAs of peroxi-some proliferator-activated receptors and liver X receptor-120572 inhumans no alteration in adipose tissue of obese and NIDDMpatientsrdquo Diabetes vol 46 no 8 pp 1319ndash1327 1997

[105] N ShawM Elholm andN Noy ldquoRetinoic acid is a high affinityselective ligand for the peroxisome proliferator-activated recep-tor 120573120575rdquo Journal of Biological Chemistry vol 278 no 43 pp41589ndash41592 2003

[106] G Wolf ldquoRetinoic acid as cause of cell proliferation or cellgrowth inhibition depending on activation of one of twodifferent nuclear receptorsrdquoNutrition Reviews vol 66 no 1 pp55ndash59 2008

[107] T T Schug D C Berry N S Shaw S N Travis and N NoyldquoOpposing effects of retinoic acid on cell growth result fromalternate activation of two different nuclear receptorsrdquo Cell vol129 no 4 pp 723ndash733 2007

[108] D C Berry and N Noy ldquoAll-trans-retinoic acid repressesobesity and insulin resistance by activating both peroxisomeproliferation-activated receptor 120573120575 and retinoic acid receptorrdquoMolecular and Cellular Biology vol 29 no 12 pp 3286ndash32962009

[109] D C Berry D DeSantis H Soltanian C M Croniger andN Noy ldquoRetinoic acid upregulates preadipocyte genes to blockadipogenesis and suppress diet-induced obesityrdquo Diabetes vol61 no 5 pp 1112ndash1121 2012

[110] M G Borland C Khozoie P P Albrecht et al ldquoStableover-expression of PPAR120573120575 and PPAR120574 to examine receptorsignaling in human HaCaT keratinocytesrdquo Cellular Signallingvol 23 no 12 pp 2039ndash2050 2011

[111] S E OrsquoSullivan and D A Kendall ldquoCannabinoid activationof peroxisome proliferator-activated receptors potential formodulation of inflammatory diseaserdquo Immunobiology vol 215no 8 pp 611ndash616 2010

[112] Z C Yan D Y Liu L L Zhang et al ldquoExercise reduces adiposetissue via cannabinoid receptor type 1 which is regulated byperoxisome proliferator-activated receptor-120575rdquo Biochemical andBiophysical Research Communications vol 354 no 2 pp 427ndash433 2007

[113] J D McGarry ldquoWhat if Minkowski had been ageusic Analternative angle on diabetesrdquo Science vol 258 no 5083 pp766ndash770 1992

[114] TMoore ldquoVitaminA and carotene the vitaminA reserve of theadult human being in health and diseaserdquo Biochemical Journalvol 31 no 1 pp 155ndash164 1937

[115] GWolfMD Lane and B C Johnson ldquoStudies on the functionof vitamin A in metabolismrdquo Journal of Biological Chemistryvol 225 no 2 pp 995ndash1008 1957

[116] Y Zhang R Li Y Li W Chen S Zhao and G Chen ldquoVitaminA status affects obesity development and hepatic expression ofkey genes for fuel metabolism in Zucker fatty ratsrdquoBiochemistryand Cell Biology vol 90 no 4 pp 548ndash557 2012

[117] M Singh V N Singh and T A Venkitasubramanian ldquoEarlyeffects of feeding excess vitamin A hepatic glycogen bloodlactic acid plasma nefa and glucose tolerance in ratsrdquo LifeSciences vol 7 no 5 pp 239ndash247 1968

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

10 ISRN Hepatology

provide a novel target for the treatment of the RA-inducedhypertriglyeridemia

323 The Effects of RA Treatment on Obesity Developmentin Mice Interestingly the RA administration in rodentscauses reduction of body mass as summarized in [212] Thiskind of reduction of body mass has been associated withenhancement of insulin sensitivity in genetic [213] or DIOmice [108] The mechanisms of RA-mediated attenuation ofinsulin resistance have been thought to be the induction ofenergy expenditure through PPAR120573120575 activation [108] andthe inhibition of adipogenesis throughRXR120574 activation [109]On the other hand retinol can be metabolized in adipose tis-sues [214]Themice with deletion ofRaldh1 gene (Raldh1minusminus)have elevated retinal in their adipose tissues and are resistantto diet-induced obesity and insulin resistance [26] This hasbeen attributed to the suppression of adipogenesis by retinal-inhibited activation of PPAR120574 and RXR [26] It is interestingto note that either retinal or RA can inhibit the adipogenesisand cause the improvement of insulin sensitivity in micebased on these studies

33 Roles of VA and Retinoids in the Regulation of HepaticLipogenic Gene Expression Insulin resistance diabetes andother metabolic abnormalities are associated with profoundchanges of hepatic lipid and glucose metabolismThis can beattributed at least in part to the altered expression of genesinvolved in glucose and lipid metabolism [215] The hepaticlipogenesis contributes to the homeostasis of FAs and TGs

331 The Regulation of Hepatic Srebp-1c Expression by VAStatus and Retinoids Treatment Insulin plays an essentialrole in the hepatic FA synthesis It has been known for a whilethat insulin is needed for the glucose usage for lipogenesis andCO2production in the liver [216] The hepatic FA synthesis

rises sharply and continuously after rats are fasted and thenrefed a high-carbohydrate diet [217] The amount of fattyacid synthase (FAS) is induced in normal rats refed a high-carbohydrate diet after fasting and in STZ-induced diabeticrats after insulin administration [218] In the insulin-deficientrats the induction of FAS after refeeding occurs only wheninsulin injection is injected [219] a process attributed to theinduction of FAS gene (Fas) [220 221]

The transcription of hepatic Fas is controlled by a tran-scription factor named SREBP-1c [222] In the liver-specificSrebp-1c knockoutmouse liver the induction of Fas and otherlipogenic genes by refeeding after fasting is blunted [223]Interestingly insulin also specifically induces the Srebp-1cexpression in the liver [224] via two liver X receptor elements(LXREs) and one sterol-responsive element (SRE) [225]However in liver-specific insulin receptor knockoutmice theinduction of hepatic Srebp-1c by refeeding largely remainedunchanged [226] This suggests that nutrient-derived signalsmay activate downstream of insulin receptor signaling path-way to regulate Srebp-1c expression and hepatic lipogenesis[226]

As stated in the previous section my research group hasobserved that the VAD ZL and ZF rats have lower plasma TG

levels than their VAS controls [116] This is accompanied bythe reduction of the hepatic expression of Srebp-1cmRNA inVA-deficient animals [116] My research group has reportedfor the first time that retinoids synergize with insulin toinduce the expression of Srebp-1c in primary rat hepatocytes[227] Further analysis of the Srebp-1c promoter reveals thatthe previous identified LXREs responsible for mediatinginsulin-induced Srebp-1c expression are also RAREs [227]These observations show that retinoids (nutritional) andinsulin (hormonal) signals converge to regulate the FAsynthesis in the liver

332 The Effects of VA Catabolism on the Regulation of Srebp-1c Expression in Primary Rat Hepatocytes More recentlyretinoids have been proposed to play roles in glucose and lipidmetabolism and to maintain energy homeostasis [228 229]VA (retinol) is reversibly converted into retinal and retinalis irreversibly converted into RA [23] Retinal the precursorof RA production is able to synergize with insulin to inducethe Srebp-1c expression in primary rat hepatocytes [227]This suggests that the dynamic production of RA influencesthe expression of hepatic lipogenic genes It has led us toinvestigate the roles of RA production in the insulin-resistantanimals

In the liver of the Raldh1minusminus mice RA production isreduced in response to a load of retinol [230] The Raldh1minusminusmice are resistant to the development of obesity and insulinresistance after being fed an HFD [26] This is attributed tothe elevation of retinal content due to the lack of conversionof retinal to RA in the adipose tissues of the Raldh1minusminusmice Additionally the liver of the Raldh1minusminus mice hasaltered regulation of the genes for gluconeogenesis andsignificantly attenuated hepatic TG synthesis indicating theimportant role of hepatic VAmetabolism in glucose and lipidhomeostasis [231]

The hepatic expression levels of RALDH1 and RALDH2are induced in mice fed a high-cholesterol diet [232] SREsare located in the promoters of these two genes whichare induced by SREBP-1c overexpression The expression ofSrebp-1c is induced by the oxysterols derived from the high-cholesterol diet [232] This research work demonstrates theinteraction of cholesterol and RA metabolism in the liver Inaddition it has been shown that the level of Raldh1mRNA iselevated in the kidney of dbdb mice [233] Both dbdb miceand ZF rats develop obesity due to the mutation of leptinreceptor [234]

In an attempt to understand the roles of VA metabolismin the states of metabolic diseases we have compared theexpression levels of enzymes responsible for the productionof retinal and RA in the freshly isolated and cultured primaryhepatocytes from ZL rats and ZF rats [45] We have foundthat in the primary rat hepatocytes the enzymes responsiblefor the conversions of retinol to retinal and from retinal toRA are most likely RDH2 and RALDH1 respectively Theexpression levels of Raldh1 mRNA and its protein are higherin hepatocytes from ZF rats than in those from ZL rats[45] When overexpressed RALDH1 introduces the retinal-mediated induction of Srebp-1c in INS-1 cells which do not

ISRN Hepatology 11

respond to retinal in our previous study [227] These resultsindicate that insulin-resistant animals such as ZF rats mayhave alterations in retinoids metabolism

Thus we have hypothesized that the change of RAproduction from the oversupply of dietary VA due to thehyperphagia of ZF rats results in higher Srebp-1c expressionin ZF hepatocytes [45] The elevated SREBP-1c expressioncan further induceRaldh1 expression to create a feed-forwardmechanism that could be one of the reasons responsible forthe increased lipogenesis in the liver of ZF rats All of theseobservations indicate the potential roles of RA metabolismin the development of obesity and insulin resistance whichdeserves to be further studied

4 VArsquos Roles in Mediating Hepatic InsulinAction and Insulin Resistance

41 Insulin and Its Signal Transduction The insulin moleculeis made of two chains linked by one intra- and one interchaindisulfide bonds [235] The insulin receptor is a transmem-brane and heterotetramer tyrosine kinase receptor (two 120572and two 120573 subunits) linked by disulfide bonds as well [236]The binding of insulin to its receptor causes conformationchanges and transphosphorylation of the 120573-subunit tyrosinekinase [237 238] which initiates the signal transduction[239] Protein-protein interactions are involved in the trans-duction of insulin signalThe signal is transduced bymultiplecomponents in a complex network containing cascades ofkinases and phosphatases [240 241] The first intracellularcomponents mediating insulin signals are insulin recep-tor substrates (IRSs) protein molecules phosphorylated byinsulin receptor 120573-subunit and mediating insulin signals[242]

The insulin signal event is further amplified byphosphatidylinositide 3-kinases (PI3K)protein kinaseB (PKBAkt) pathway and GRB2mitogen-activated proteinkinase (MAPK) pathway [243ndash245] Another serinethre-onine kinase that can be activated by PI3K is the atypicalprotein kinase C [246] Human liver expresses severalprotein-tyrosine phosphatases (PTPs) [247] Okadai acid aninhibitor of protein phosphatase type 2A and type 1 inhibitsglycogen synthesis and insulin-stimulated Gck expression inprimary rat hepatocytes indicating that dephosphorylationmechanism may also participate in mediating insulinsignaling [248] These components are shared by insulin-likegrowth factor (IGF) receptor and involved in mediatinginsulin and IGF signals [249]

42 Metabolic Diseases and Insulin Resistance The rise ofthe number of people with one or more metabolic diseasessuch as obesity and diabetes in the world has become apublic health problem [250] The interactions of genetic andenvironmentalnutritional factors may be responsible for thecurrent rise of metabolic diseases The long evolutionaryprocess has equipped human and animal bodieswith a varietyof regulatory mechanisms controlling these interactions [251252] Human diets contain not only energy derived frommacronutrients but also micronutrients and other factors

which may influence the metabolic outcomes The roles ofindividual micronutrients in the development of metabolicdiseases are still unrevealed

One common property of human obesity and NIDDMis insulin resistance in which a given amount of insulinproduces less than normal physiological responses Dietaryfactors and manipulations have been considered to play arole in the development of insulin resistance in humans andanimals For example feeding an HFD to young and insulin-sensitive subjects for two days causes the development ofglucose intolerance [253] In the skeletal muscle of rats fedan HFD for 8 weeks the insulin-induced glucose uptakeis impaired [254] FFAs have been considered the factorsresponsible for HFD-induced leptin and insulin resistance[255ndash257]

43 Hepatic Insulin Resistance and Vicious Cycle The liverplays an essential role in the control of glucose andlipid homeostasis It coordinately regulates the processesin responses to nutritional and hormonal stimuli Insulinplays a major role in directing the liverrsquos metabolic status[258] which is partially attributed to the regulation of theexpression of genes involved in hepatic glucose and lipidmetabolism [215 259]

Insulin controls the expression of a variety of genesinvolved in glycolysis glycogenesis and lipogenesis andgluconeogenesis in the liver [145] Generally hepatic lipidand glucose metabolism is altered with the development ofinsulin resistance in obesity and NIDDM [258] This canbe reflected in the expression of insulin-regulated hepaticgenes for glucose and FA metabolism When the liver isinsulin sensitive insulin stimulates lipogenesis and inhibitsgluconeogenesis For example to regulate hepatic glucosehomeostasis insulin increases the expression of Gck gene[119 120] and Srebp-1c [224] a family member of SREBPswhich regulate the hepatic cholesterol and FA biosynthesisand their homeostasis [260] It suppresses the expressionof Pck1 [142] and G6pc [145] which control the first andlast steps of gluconeogenesis respectively When the liver isinsulin resistant insulin no longer inhibits gluconeogenesisHowever the liver still keeps the elevated lipogenesis Theelevated FA biosynthesis in the insulin-resistant state furtherfacilitates insulin secretion from pancreatic 120573-cells whichprobably enhances lipogenesis and results in a vicious cycle[113 261] The coexistence of the hepatic insulin resistanceand sensitivity at the gene expression level has been observedin rodent obese and diabetic models [215 258] Howeverthe mechanism of this coexistence of insulin sensitivity andresistance has not been revealed [261]

Recently the SREBP cleavage-activating protein gene(Scap) an escort protein necessary for generating nuclearforms of SREBPs has been knocked out in insulin-resistantobob mice [262] Deficiency of hepatic Scap reverses liverlipogenesis and steatosis in obobmice However the plasmalevels of glucose and insulin and the hepatic expression levelsof Pck1 andG6pcwere not different between the control obobmice and the obob mice with liver-specific Scap knockout[262] It seems that the suppression of hepatic FA synthesis

12 ISRN Hepatology

is not sufficient to correct insulin resistance Whether otherfactors play a role in the hepatic insulin resistance is still anopen question

The clinical use of RA-based medicine such asisotretinoin (13-cis RA) caused elevation of plasma TGlevels in human subjects [195ndash197] This increase in plasmaTG levels is also observed in rats [201ndash203] From our VAstatus studies we have shown that VA status affected theobesity development in ZF rats and reduced plasma insulinand TG levels in ZL and ZF rats suggesting improvement ofinsulin sensitivity [116] The hepatic expression of Srebp-1cwas reduced in VA-deficient animals [116] RA synergizeswith insulin to induce the expression of Srebp-1c in primaryrat hepatocytes [227] On the other hand RA treatmentinduces Pck1 expression and attenuates insulin-mediatedsuppression of its expression in primary rat hepatocytes [172]All of these observations demonstrate that RA attenuatesinsulin action (insulin-suppressed Pck1 expression) andstill promotes insulin action (insulin-induced Srebp-1cexpression) in the same primary hepatocytes

44 Possible Mechanism by Which RA Production Causes theDevelopment of the Vicious Cycle in Hepatocytes Could RAor other metabolites from VA catabolism be a factor thatcontributes to the hepatic insulin resistance and the viciouscycleUsing the regulation ofPck1 and Srebp-1c as themodel Ihave come upwith the following scheme to show that retinoidmetabolism could be a factor that causes the vicious cycle inthe liver As shown in Figure 3(a) in insulin-sensitive hepa-tocytes RA derived from retinal coordinates with insulin toregulate the expression of Srebp-1c and Pck1 The SREBP-1cprotein is processed to mature form a step that can be facili-tated by insulin [263] The mature form of SREBP-1c entersinto the nucleus and induces the mRNA levels of Raldh1and Fas which are respectively transcribed into RALDH1and FAS RALDH1 catalyzes the conversion of retinal to RAFAS catalyzes the synthesis of palmitate which is esterifiedinto TGs or elongated to longer FAs The Pck1 mRNA isused to translate into PEPCK-C protein which contributesto glucogenogenesis In the insulin-resistant hepatocytes asshown in Figure 3(b) the elevation of Raldh1 expressiondue to leptin deficiency [45] or induction of SREBP-1c byhigh-cholesterol feeding [232] induces the production of RAThe elevated RA levels will stimulate the transcription ofSrebp-1c and Pck1 This leads to more production of SREBP-1c and its mature form in the presence of higher insulinlevels in the insulin-resistant state The induction of SREBP-1c further enhances the transcription of Raldh1 and Fas andtheir corresponding proteins for the production of moreRAs and FAs respectively The RA production and SREBP-1c expression form a feed-forward cycle which causes moreTG and RA production in the insulin-resistant liver At thesame time more of the PEPCK-C protein is generated dueto the elevated Pck1 transcription by RA stimulation whichis not responsive to insulin inhibition as we have shown in[172] This leads to elevated gluconeogenesis in the insulin-resistant liver Eventually the phenotypes appear as if insulin

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1cRetinal

RALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(a) Insulin-sensitive hepatocytes

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1c

RetinalRALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(b) Insulin-resistant hepatocytes

Figure 3 The effects of RA on the insulin-regulated Srebp-1cand Pck1 expression levels the protein levels of SREBP-1c theexpression levels of Raldh1 and Fas and the fatty acid synthesisand gluconeogenesis in insulin-sensitive (a) and insulin-resistant (b)hepatocytes Please see the text in this paper for description Uparrows next to the text indicate induction The intensified weight ofthe lines indicates the induction of that part of the pathway

no longer suppresses gluconeogenesis while it still stimulatesFA synthesis in the insulin-resistant state

5 Perspectives and Future Directions

I have proposed a mechanism by which VA metabolismcontributes to the development of hepatic insulin resistanceIt explains some observations reported in the previous studiesof rodent obese and diabetic models [215 258] However itleavesmore open questionsThefirst one iswhat the initiationfactor is So far the elevated expression of Raldh1 mRNA inthe liver has been observed in ZF rats [45] and mice fed ahigh-cholesterol diet [232] These two conditions cause a lotof physiological changes such as overfeeding in ZF rats andchange of cholesterol biosynthesis in response to the feedingof high-cholesterol diet Knocking down Raldh1 specificallyin hepatocytes is needed to answer these questions The

ISRN Hepatology 13

second question is whether RA synthesis in hepatocytesis a regulated process in response to dietary or hormonalstimulations If Raldh1 is a downstream gene of SREBP-1cit should be regulated when the SREBP-1c level changes Asthe expression of Srebp-1c responds to insulin stimulation andoxysterols the regulation of Raldh1 expression in the livershould be studied The third question is why it is RALDH1but not other RALDHs Specific inhibitors of RALDHsmay be needed to answer this question Last question iswhether we can attenuate insulin resistance by suppressingthe RALDH1 activity in the liver It has been shown thatRaldh1minusminus mice are still insulin sensitive when they are onan HFD [26] This has been attributed to the effects on theadipogenesis However the liver of those knockout mice hasreduced lipid synthesis [231] Further studies are warrantedto answer all of these questions Hopefully it can become anintervention point for the treatment of insulin resistance andmetabolic diseases

Acknowledgments

This work was financially supported by a research grantfrom Allen Foundation Inc (to Guoxun Chen) a start-up fund from the University of Tennessee at Knoxville (toGuoxun Chen) and a Scientist Development Grant fromthe AmericanHeart Association (09SDG2140003 to GuoxunChen) The author thanks his colleague Dr Lauren Gellar forreading through this paper and offering her edits

References

[1] F G Hopkins ldquoFeeding experiments illustrating the impor-tance of accessory factors in normal dietariesrdquo The Journal ofPhysiology vol 44 no 5-6 pp 425ndash460 1912

[2] K J Carpenter ldquoA short history of nutritional science part 3(1912ndash1944)rdquo Journal of Nutrition vol 133 no 10 pp 3023ndash30322003

[3] E V McCollum and M Davis ldquoThe necessity of certain lipinsin the diet during growthrdquo Journal of Biological Chemistry vol15 no 1 pp 167ndash175 1913

[4] T B Osborne and L B Mendel ldquoFeeding experiments with fat-free food mixturesrdquo Journal of Biological Chemistry vol 12 no1 pp 81ndash89 1912

[5] R D Semba ldquoOn the lsquoDiscoveryrsquo of Vitamin Ardquo Annals ofNutrition and Metabolism vol 61 no 3 pp 192ndash198 2012

[6] R Blomhoff and H K Blomhoff ldquoOverview of retinoidmetabolism and functionrdquo Journal of Neurobiology vol 66 no7 pp 606ndash630 2006

[7] A Sommer ldquoVitamin A deficiency and clinical disease anhistorical overviewrdquo Journal of Nutrition vol 138 no 10 pp1835ndash1839 2008

[8] K J Rothman L L Moore M R Singer U-S Nguyen SMannino and A Milunsky ldquoTeratogenicity of high vitamin Aintakerdquo The New England Journal of Medicine vol 333 no 21pp 1369ndash1373 1995

[9] S Bershad A Rubinstein and J R Paterniti Jr ldquoChanges inplasma lipids and lipoproteins during isotretinoin therapy foracnerdquoThe New England Journal of Medicine vol 313 no 16 pp981ndash985 1985

[10] N Rodondi R Darioli A-A Ramelet et al ldquoHigh risk forhyperlipidemia and the metabolic syndrome after an episodeof hypertriglyceridemia during 13-cis retinoic acid therapy foracne a pharmacogenetic studyrdquo Annals of Internal Medicinevol 136 no 8 pp 582ndash589 2002

[11] H-U Klor A Weizel M Augustin et al ldquoThe impact oforal vitamin A derivatives on lipid metabolism what recom-mendations can be derived for dealing with this issue in thedaily dermatological practicerdquo Journal of the German Societyof Dermatology vol 9 no 8 pp 600ndash607 2011

[12] R M Russell ldquoThe vitamin A spectrum from deficiency totoxicityrdquoThe American Journal of Clinical Nutrition vol 71 no4 pp 878ndash884 2000

[13] A C Ross B Caballero R J Cousins K L Tucker and T RZiegler Modern Nutrition in Health and Diseases 11th edition2012

[14] E H Harrison ldquoMechanisms of digestion and absorption ofdietary vitamin Ardquo Annual Review of Nutrition vol 25 no 1pp 87ndash103 2005

[15] M R Lakshman ldquoAlpha and omega of carotenoid cleavagerdquoJournal of Nutrition vol 134 no 1 pp 241ndash245 2004

[16] I Potrykus ldquoNutritionally enhanced rice to combat malnutri-tion disorders of the poorrdquo Nutrition Reviews vol 61 no 6 ppS101ndashS104 2003

[17] A Wyss ldquoCarotene oxygenases a new family of double bondcleavage enzymesrdquo Journal of Nutrition vol 134 no 1 pp 246ndash250 2004

[18] R Kawaguchi J Yu J Honda et al ldquoA membrane receptor forretinol binding protein mediates cellular uptake of vitamin ArdquoScience vol 315 no 5813 pp 820ndash825 2007

[19] P Alapatt F Guo S M Komanetsky et al ldquoLiver retinoltransporter and receptor for serum retinol-binding protein(RBP4)rdquo Journal of Biological Chemistry vol 288 no 2 pp1250ndash1265 2013

[20] A R Moise N Noy K Palczewski and W S Blaner ldquoDeliveryof retinoid-based therapies to target tissuesrdquo Biochemistry vol46 no 15 pp 4449ndash4458 2007

[21] G Duester ldquoFamilies of retinoid dehydrogenases regulatingvitamin A function Production of visual pigment and retinoicacidrdquo European Journal of Biochemistry vol 267 no 14 pp4315ndash4324 2000

[22] M Theodosiou V Laudet and M Schubert ldquoFrom carrotto clinic an overview of the retinoic acid signaling pathwayrdquoCellular andMolecular Life Sciences vol 67 no 9 pp 1423ndash14452010

[23] J L Napoli ldquoInteractions of retinoid binding proteins andenzymes in retinoidmetabolismrdquoBiochimica et BiophysicaActavol 1440 no 2-3 pp 139ndash162 1999

[24] X Chai M H E M Boerman Y Zhai and J L NapolildquoCloning of a cDNA for liver microsomal retinol dehydro-genase A tissue-specific short-chain alcohol dehydrogenaserdquoJournal of Biological Chemistry vol 270 no 8 pp 3900ndash39041995

[25] B X Wu G Moiseyev Y Chen B Rohrer R K Crouch andJ-XMa ldquoIdentification of RDH10 an all-trans retinol dehydro-genase in retinal Muller cellsrdquo Investigative Ophthalmology andVisual Science vol 45 no 11 pp 3857ndash3862 2004

[26] O Ziouzenkova G Orasanu M Sharlach et al ldquoRetinalde-hyde represses adipogenesis and diet-induced obesityrdquo NatureMedicine vol 13 no 6 pp 695ndash702 2007

14 ISRN Hepatology

[27] J L Napoli ldquoPhysiological insights into all-trans-retinoic acidbiosynthesisrdquo Biochimica et Biophysica Acta vol 1821 no 1 pp152ndash167 2012

[28] G Wolf ldquoTissue-specific increases in endogenous all-transretinoic acid possible contributing factor in ethanol toxicityrdquoNutrition Reviews vol 68 no 11 pp 689ndash692 2010

[29] P V Bhat J Labrecque JM Boutin A Lacroix andA YoshidaldquoCloning of a cDNA encoding rat aldehyde dehydrogenase withhigh activity for retinal oxidationrdquoGene vol 166 no 2 pp 303ndash306 1995

[30] M Lin M Zhang M Abraham S M Smith and J LNapoli ldquoMouse retinal dehydrogenase 4 (RALDH4) molecularcloning cellular expression and activity in 9-cis-retinoic acidbiosynthesis in intact cellsrdquo Journal of Biological Chemistry vol278 no 11 pp 9856ndash9861 2003

[31] F A Mic A Molotkov X Fan A E Cuenca and GDuester ldquoRALDH3 a retinaldehyde dehydrogenase that gener-ates retinoic acid is expressed in the ventral retina otic vesicleand olfactory pit during mouse developmentrdquo Mechanisms ofDevelopment vol 97 no 1-2 pp 227ndash230 2000

[32] X Wang P Penzes and J L Napoli ldquoCloning of a cDNAencoding an aldehyde dehydrogenase and its expression inEscherichia coli recognition of retinal as substraterdquo Journal ofBiological Chemistry vol 271 no 27 pp 16288ndash16293 1996

[33] A Molotkov and G Duester ldquoGenetic evidence that retinalde-hyde dehydrogenase Raldh1 (Aldh1a1) functions downstreamof alcohol dehydrogenase Adh1 in metabolism of retinol toretinoic acidrdquo Journal of Biological Chemistry vol 278 no 38pp 36085ndash36090 2003

[34] G Elizondo J Corchero E Sterneck and F J GonzalezldquoFeedback inhibition of the retinaldehyde dehydrogenase geneALDH1 by retinoic acid through retinoic acid receptor 120572and CCAATenhancer-binding protein 120573rdquo Journal of BiologicalChemistry vol 275 no 50 pp 39747ndash39753 2000

[35] G Elizondo I M Medina-Dıaz R Cruz F J Gonzalez and LVega ldquoRetinoic acid modulates retinaldehyde dehydrogenase 1gene expression through the induction of GADD153-CEBP120573interactionrdquo Biochemical Pharmacology vol 77 no 2 pp 248ndash257 2009

[36] K Fujiwara M Kikuchi K Horiguchi et al ldquoEstrogen receptoralpha regulates retinaldehyde dehydrogenase 1 expression in ratanterior pituitary cellsrdquo Endocrine Journal vol 56 no 8 pp963ndash973 2009

[37] K Fujiwara F Maekawa M Kikuchi S Takigami T Yadaand T Yashiro ldquoExpression of retinaldehyde dehydrogenase(RALDH)2 and RALDH3 but not RALDH1 in the developinganterior pituitary glands of ratsrdquo Cell and Tissue Research vol328 no 1 pp 129ndash135 2007

[38] GWolf ldquoThe enzymatic cleavage of 120573-carotene still controver-sialrdquo Nutrition Reviews vol 53 no 5 pp 134ndash137 1995

[39] S Abu-Abed P Dolle D Metzger B Beckett P Chambonand M Petkovich ldquoThe retinoic acid-metabolizing enzymeCYP26A1 is essential for normal hindbrain patterning verte-bral identity and development of posterior structuresrdquo Genesand Development vol 15 no 2 pp 226ndash240 2001

[40] M A Leo S Iida and C S Lieber ldquoRetinoic acid metabolismby a system reconstituted with cytochrome P-450rdquo Archives ofBiochemistry and Biophysics vol 234 no 1 pp 305ndash312 1984

[41] MA Leo JM Lasker J L Raucy C-I KimM Black andC SLieber ldquoMetabolism of retinol and retinoic acid by human livercytochrome P450IIC8rdquoArchives of Biochemistry and Biophysicsvol 269 no 1 pp 305ndash312 1989

[42] R Quere A Baudet B Cassinat et al ldquoPharmacogenomicanalysis of acute promyelocytic leukemia cells highlightsCYP26cytochrome metabolism in differential all-trans retinoic acidsensitivityrdquo Blood vol 109 no 10 pp 4450ndash4460 2007

[43] J AWhite B Beckett-Jones Y-D Guo et al ldquocDNA cloning ofhuman retinoic acid-metabolizing enzyme (hP450RAI) identi-fies a novel family of cytochromes p450 (CYP26)rdquo Journal ofBiological Chemistry vol 272 no 30 pp 18538ndash18541 1997

[44] Y Zhang R Zolfaghari Reza and A C Ross ldquoMultiple retinoicacid response elements cooperate to enhance the inducibility ofCYP26A1 gene expression in liverrdquo Gene vol 464 no 1-2 pp32ndash43 2010

[45] Y Li Y Zhang R Li et al ldquoThe hepatic raldh1 expression iselevated in Zucker fatty rats and its over-expression introducedthe retinal-induced Srebp-1c expression in INS-1 cellsrdquo PLoSONE vol 7 no 9 Article ID e45210 2012

[46] R M Evans ldquoThe nuclear receptor superfamily a Rosetta stonefor physiologyrdquo Molecular Endocrinology vol 19 no 6 pp1429ndash1438 2005

[47] P Chambon ldquoA decade of molecular biology of retinoic acidreceptorsrdquo FASEB Journal vol 10 no 9 pp 940ndash954 1996

[48] D J Mangelsdorf and RM Evans ldquoThe RXR heterodimers andorphan receptorsrdquo Cell vol 83 no 6 pp 841ndash850 1995

[49] J E Balmer and R Blomhoff ldquoA robust characterization ofretinoic acid response elements based on a comparison of sitesin three speciesrdquo Journal of Steroid Biochemistry and MolecularBiology vol 96 no 5 pp 347ndash354 2005

[50] R Kurokawa J DiRenzo M Boehm et al ldquoRegulation ofretinoid signalling by receptor polarity and allosteric control ofligand bindingrdquo Nature vol 371 no 6497 pp 528ndash531 1994

[51] A Cvekl and W-L Wang ldquoRetinoic acid signaling in mam-malian eye developmentrdquo Experimental Eye Research vol 89no 3 pp 280ndash291 2009

[52] V Dupe M Davenne J Brocard et al ldquoIn vivo functional anal-ysis of the Hoxa-1 31015840 retinoic acid response element (31015840RARE)rdquoDevelopment vol 124 no 2 pp 399ndash410 1997

[53] A C Ross ldquoRetinoid production and catabolism role of dietin regulating retinol esterification and retinoic acid oxidationrdquoJournal of Nutrition vol 133 no 1 pp 291ndash296 2003

[54] T Moore and P D Holmes ldquoThe production of experimentalvitamin A deficiency in rats andmicerdquo Laboratory Animals vol5 no 2 pp 239ndash250 1971

[55] A C Ross and E H Harrison ldquoVitamin A and carotenoidsrdquoin Handbook of Vitamins D E McCormick R R Rucker J WSuttie et al Eds CRC Press Boca Raton Fla USA 4th edition2006

[56] A Chawta J J Repa R M Evans and D J MangelsdorfldquoNuclear receptors and lipid physiology opening the x-filesrdquoScience vol 294 no 5548 pp 1866ndash1870 2001

[57] C K Glass and M G Rosenfeld ldquoThe coregulator exchangein transcriptional functions of nuclear receptorsrdquo Genes andDevelopment vol 14 no 2 pp 121ndash141 2000

[58] A L Bookout Y Jeong M Downes R T Yu R M EvansandD JMangelsdorf ldquoAnatomical profiling of nuclear receptorexpression reveals a hierarchical transcriptional networkrdquo Cellvol 126 no 4 pp 789ndash799 2006

[59] B Mascrez M Mark W Krezel et al ldquoDifferential contribu-tions of AF-1 andAF-2 activities to the developmental functionsof RXR120572rdquo Development vol 128 no 11 pp 2049ndash2062 2001

[60] D Li T Li F Wang H Tian and H H Samuels ldquoFunctionalevidence for retinoid X receptor (RXR) as a nonsilent partner

ISRN Hepatology 15

in the thyroid hormone receptorRXR heterodimerrdquoMolecularand Cellular Biology vol 22 no 16 pp 5782ndash5792 2002

[61] F M Sladek W Zhong E Lai and J E Darnell Jr ldquoLiver-enriched transcription factor HNF-4 is a novel member ofthe steroid hormone receptor superfamilyrdquo Genes and Develop-ment vol 4 no 12 pp 2353ndash2365 1990

[62] K Yamagata H Furuta N Oda et al ldquoMutations in thehepatocyte nuclear factor-4120572 gene inmaturity-onset diabetes ofthe young (MODY1)rdquo Nature vol 384 no 6608 pp 458ndash4601996

[63] M Stoffel and S ADuncan ldquoThematurity-onset diabetes of theyoung (MODY1) transcription factor HNF4120572 regulates expres-sion of genes required for glucose transport and metabolismrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 24 pp 13209ndash13214 1997

[64] M Lehto P-O Bitzen B Isomaa et al ldquoMutation in the HNF-4120572 gene affects insulin secretion and triglyceride metabolismrdquoDiabetes vol 48 no 2 pp 423ndash425 1999

[65] G P Hayhurst Y-H Lee G Lambert J M Ward and F JGonzalez ldquoHepatocyte nuclear factor 4120572 (Nuclear receptor 2A1)is essential formaintenance of hepatic gene expression and lipidhomeostasisrdquo Molecular and Cellular Biology vol 21 no 4 pp1393ndash1403 2001

[66] U Roth K Jungermann and T Kietzmann ldquoActivation ofglucokinase gene expression by hepatic nuclear factor 4120572 inprimary hepatocytesrdquo Biochemical Journal vol 365 no 1 pp223ndash228 2002

[67] S Mandard R Stienstra P Escher et al ldquoGlycogen synthase2 is a novel target gene of peroxisome proliferator-activatedreceptorsrdquo Cellular and Molecular Life Sciences vol 64 no 9pp 1145ndash1157 2007

[68] F Rajas A Gautier I Bady S Montano and G MithieuxldquoPolyunsaturated fatty acyl coenzyme a suppress the glucose-6-phosphatase promoter activity bymodulating the DNA bindingof hepatocyte nuclear factor 4120572rdquo Journal of Biological Chemistryvol 277 no 18 pp 15736ndash15744 2002

[69] B Viollet A Kahn and M Raymondjean ldquoProtein kinase A-dependent phosphorylation modulates DNA-binding activityof hepatocyte nuclear factor 4rdquoMolecular and Cellular Biologyvol 17 no 8 pp 4208ndash4219 1997

[70] L Palanker J M Tennessen G Lam and C S Thum-mel ldquoDrosophila HNF4 regulates lipid mobilization and 120573-oxidationrdquo Cell Metabolism vol 9 no 3 pp 228ndash239 2009

[71] A Miura K Yamagata M Kakei et al ldquoHepatocyte nuclearfactor-4120572 is essential for glucose-stimulated insulin secretion bypancreatic 120573-cellsrdquo Journal of Biological Chemistry vol 281 no8 pp 5246ndash5257 2006

[72] R Bartoov-Shifman R Hertz H Wang C B Wollheim JBar-Tana and M D Walker ldquoActivation of the insulin genepromoter through a direct effect of hepatocyte nuclear factor4120572rdquo Journal of Biological Chemistry vol 277 no 29 pp 25914ndash25919 2002

[73] H Wang P Maechler P A Antinozzi K A Hagenfeldt andC B Wollheim ldquoHepatocyte nuclear factor 4120572 regulates theexpression of pancreatic 120573-cell genes implicated in glucosemetabolism and nutrient-induced insulin secretionrdquo Journal ofBiological Chemistry vol 275 no 46 pp 35953ndash35959 2000

[74] K Reue T Leff and J L Breslow ldquoHuman apolipoproteinCIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factorsrdquo Journal ofBiological Chemistry vol 263 no 14 pp 6857ndash6864 1988

[75] T Leff K Reue A Melian H Culver and J L BreslowldquoA regulatory element in the apoCIII promoter that directshepatic specific transcription binds to proteins in expressingand nonexpressing cell typesrdquo Journal of Biological Chemistryvol 264 no 27 pp 16132ndash16137 1989

[76] S N Lavrentiadou M Hadzopoulou-Cladaras D Kardassisand V I Zannis ldquoBinding specificity and modulation of thehuman apocIII promoter activity by heterodimers of ligand-dependent nuclear receptorsrdquo Biochemistry vol 38 no 3 pp964ndash975 1999

[77] T R Magee Y Cai M E El-Houseini J Locker and Y-JY Wan ldquoRetinoic acid mediates down-regulation of the 120572-fetoprotein gene through decreased expression of hepatocytenuclear factorsrdquo Journal of Biological Chemistry vol 273 no 45pp 30024ndash30032 1998

[78] A Qian Y Cai T R Magee and Y J Y Wan ldquoIdentificationof retinoic acid-responsive elements on the HNF1alpha andHNF4alpha genesrdquo Biochemical and Biophysical Research Com-munications vol 276 no 3 pp 837ndash842 2000

[79] H Nakshatri and P Chambon ldquoThe directly repeatedRG(GT)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites forRAR RXR HNF-4 and ARP-1 homo- and heterodimersrdquoJournal of Biological Chemistry vol 269 no 2 pp 890ndash9021994

[80] T Makita G Hernandez-Hoyos T H-P Chen H Wu E VRothenberg and H M Sucov ldquoA developmental transition indefinitive erythropoiesis erythropoietin expression is sequen-tially regulated by retinoic acid receptors andHNF4rdquoGenes andDevelopment vol 15 no 7 pp 889ndash901 2001

[81] T I Kambe J Tada-Kambe Y Kuge Y Yamaguchi-Iwai MNagao and R Sasaki ldquoRetinoic acid stimulates erythropoietingene transcription in embryonal carcinoma cells through thedirect repeat of a steroidthyroid hormone receptor responseelement half-site in the hypoxia-response enhancerrdquo Blood vol96 no 9 pp 3265ndash3271 2000

[82] F-J Lin J Qin K Tang S Y Tsai and M-J Tsai ldquoCoup drsquoEtatan orphan takes controlrdquo Endocrine Reviews vol 32 no 3 pp404ndash421 2011

[83] L-H Wang S Y Tsai R G Cook W G Beattie M-J Tsaiand BW OrsquoMalley ldquoCOUP transcription factor is a member ofthe steroid receptor superfamilyrdquoNature vol 340 no 6229 pp163ndash166 1989

[84] X Leng A J Cooney S Y Tsai and M-J Tsai ldquoMolecularmechanisms of COUP-TF-mediated transcriptional repressionevidence for transrepression and active repressionrdquo Molecularand Cellular Biology vol 16 no 5 pp 2332ndash2340 1996

[85] L Li X Xie J Qin et al ldquoThe nuclear orphan receptorCOUP-TFII plays an essential role in adipogenesis glucosehomeostasis and energy metabolismrdquo Cell Metabolism vol 9no 1 pp 77ndash87 2009

[86] F A Pereira Q Yuhong G Zhou M-J Tsai and S YTsai ldquoThe orphan nuclear receptor COUP-TFII is required forangiogenesis and heart developmentrdquo Genes and Developmentvol 13 no 8 pp 1037ndash1049 1999

[87] N Takamoto I Kurihara K Lee F J DeMayo M-J Tsai andS Y Tsai ldquoHaploinsufficiency of chicken ovalbumin upstreampromoter transcription factor II in female reproductionrdquoMolec-ular Endocrinology vol 19 no 9 pp 2299ndash2308 2005

[88] P Zhang M Bennoun C Gogard et al ldquoExpression of COUP-TFII in metabolic tissues during developmentrdquo Mechanisms ofDevelopment vol 119 no 1 pp 109ndash114 2002

16 ISRN Hepatology

[89] Z Xu S Yu C-H Hsu J Eguchi and E D Rosen ldquoTheorphan nuclear receptor chicken ovalbumin upstream pro-moter-transcription factor II is a critical regulator of adipogene-sisrdquoProceedings of theNationalAcademy of Sciences of theUnitedStates of America vol 105 no 7 pp 2421ndash2426 2008

[90] P Bardoux P Zhang D Flamez et al ldquoEssential role of chickenovalbumin upstreampromoter-transcription factor II in insulinsecretion and insulin sensitivity revealed by conditional geneknockoutrdquo Diabetes vol 54 no 5 pp 1357ndash1363 2005

[91] G Achatz B Holzl R Speckmayer C Hauser F Sandhoferand B Paulweber ldquoFunctional domains of the human orphanreceptor ARP-1COUP-TFII involved in active repression andtransrepressionrdquo Molecular and Cellular Biology vol 17 no 9pp 4914ndash4932 1997

[92] S A Kliewer K Umesono R A Heyman D J MangelsdorfJ A Dyck and R M Evans ldquoRetinoid X receptor-COUP-TFinteractionsmodulate retinoic acid signalingrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol89 no 4 pp 1448ndash1452 1992

[93] A J Cooney S Y Tsai BW OrsquoMalley andM-J Tsai ldquoChickenovalbumin upstreampromoter transcription factor (COUP-TF)dimers bind to different GGTCA response elements allowingCOUP-TF to repress hormonal induction of the vitamin D3thyroid hormone and retinoic acid receptorsrdquo Molecular andCellular Biology vol 12 no 9 pp 4153ndash4163 1992

[94] SW Kruse K Suino-Powell X E Zhou et al ldquoIdentification ofCOUP-TFII orphannuclear receptor as a retinoic acid-activatedreceptorrdquo PLoS Biology vol 6 no 9 Article ID e227 2008

[95] J P Berger T E Akiyama and P T Meinke ldquoPPARs thera-peutic targets for metabolic diseaserdquo Trends in PharmacologicalSciences vol 26 no 5 pp 244ndash251 2005

[96] JM Peters andF J Gonzalez ldquoSorting out the functional role(s)of peroxisome proliferator-activated receptor-120573120575 (PPAR120573120575)in cell proliferation and cancerrdquo Biochimica et Biophysica Actavol 1796 no 2 pp 230ndash241 2009

[97] A Tenenbaum and E Fisman ldquoBalanced pan-PPAR activatorbezafibrate in combination with statin comprehensive lipidscontrol and diabetes preventionrdquo Cardiovascular Diabetologyvol 11 no 1 article 140 2012

[98] O Braissant F Foufelle C Scotto M Dauca and W WahlildquoDifferential expression of peroxisome proliferator-activatedreceptors (PPARs) tissue distribution of PPAR-120572 -120573 and -120574 inthe adult ratrdquo Endocrinology vol 137 no 1 pp 354ndash366 1996

[99] H Higashiyama A N Billin Y Okamoto M Kinoshita andS Asano ldquoExpression profiling of Peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues usingtissue microarrayrdquo Histochemistry and Cell Biology vol 127 no5 pp 485ndash494 2007

[100] P S Jones R Savory P Barratt et al ldquoChromosomal local-isation inducibility tissue-specific expression and strain dif-ferences in three murine peroxisome-proliferator-activated-receptor genesrdquo European Journal of Biochemistry vol 233 no1 pp 219ndash226 1995

[101] S A Kliewer B M Forman B Blumberg et al ldquoDifferentialexpression and activation of a family of murine peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no15 pp 7355ndash7359 1994

[102] E E Girroir H E Hollingshead P He B Zhu G H Perdewand J M Peters ldquoQuantitative expression patterns of peroxi-some proliferator-activated receptor-120573120575 (PPAR120573120575) protein in

micerdquo Biochemical and Biophysical Research Communicationsvol 371 no 3 pp 456ndash461 2008

[103] P Escher O Braissant S Basu-Modak L Michalik W Wahliand B Desvergne ldquoRat PPARs quantitative analysis in adult rattissues and regulation in fasting and refeedingrdquo Endocrinologyvol 142 no 10 pp 4195ndash4202 2001

[104] D Auboeuf J Rieusset L Fajas et al ldquoTissue distributionand quantification of the expression of mRNAs of peroxi-some proliferator-activated receptors and liver X receptor-120572 inhumans no alteration in adipose tissue of obese and NIDDMpatientsrdquo Diabetes vol 46 no 8 pp 1319ndash1327 1997

[105] N ShawM Elholm andN Noy ldquoRetinoic acid is a high affinityselective ligand for the peroxisome proliferator-activated recep-tor 120573120575rdquo Journal of Biological Chemistry vol 278 no 43 pp41589ndash41592 2003

[106] G Wolf ldquoRetinoic acid as cause of cell proliferation or cellgrowth inhibition depending on activation of one of twodifferent nuclear receptorsrdquoNutrition Reviews vol 66 no 1 pp55ndash59 2008

[107] T T Schug D C Berry N S Shaw S N Travis and N NoyldquoOpposing effects of retinoic acid on cell growth result fromalternate activation of two different nuclear receptorsrdquo Cell vol129 no 4 pp 723ndash733 2007

[108] D C Berry and N Noy ldquoAll-trans-retinoic acid repressesobesity and insulin resistance by activating both peroxisomeproliferation-activated receptor 120573120575 and retinoic acid receptorrdquoMolecular and Cellular Biology vol 29 no 12 pp 3286ndash32962009

[109] D C Berry D DeSantis H Soltanian C M Croniger andN Noy ldquoRetinoic acid upregulates preadipocyte genes to blockadipogenesis and suppress diet-induced obesityrdquo Diabetes vol61 no 5 pp 1112ndash1121 2012

[110] M G Borland C Khozoie P P Albrecht et al ldquoStableover-expression of PPAR120573120575 and PPAR120574 to examine receptorsignaling in human HaCaT keratinocytesrdquo Cellular Signallingvol 23 no 12 pp 2039ndash2050 2011

[111] S E OrsquoSullivan and D A Kendall ldquoCannabinoid activationof peroxisome proliferator-activated receptors potential formodulation of inflammatory diseaserdquo Immunobiology vol 215no 8 pp 611ndash616 2010

[112] Z C Yan D Y Liu L L Zhang et al ldquoExercise reduces adiposetissue via cannabinoid receptor type 1 which is regulated byperoxisome proliferator-activated receptor-120575rdquo Biochemical andBiophysical Research Communications vol 354 no 2 pp 427ndash433 2007

[113] J D McGarry ldquoWhat if Minkowski had been ageusic Analternative angle on diabetesrdquo Science vol 258 no 5083 pp766ndash770 1992

[114] TMoore ldquoVitaminA and carotene the vitaminA reserve of theadult human being in health and diseaserdquo Biochemical Journalvol 31 no 1 pp 155ndash164 1937

[115] GWolfMD Lane and B C Johnson ldquoStudies on the functionof vitamin A in metabolismrdquo Journal of Biological Chemistryvol 225 no 2 pp 995ndash1008 1957

[116] Y Zhang R Li Y Li W Chen S Zhao and G Chen ldquoVitaminA status affects obesity development and hepatic expression ofkey genes for fuel metabolism in Zucker fatty ratsrdquoBiochemistryand Cell Biology vol 90 no 4 pp 548ndash557 2012

[117] M Singh V N Singh and T A Venkitasubramanian ldquoEarlyeffects of feeding excess vitamin A hepatic glycogen bloodlactic acid plasma nefa and glucose tolerance in ratsrdquo LifeSciences vol 7 no 5 pp 239ndash247 1968

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Hepatology 11

respond to retinal in our previous study [227] These resultsindicate that insulin-resistant animals such as ZF rats mayhave alterations in retinoids metabolism

Thus we have hypothesized that the change of RAproduction from the oversupply of dietary VA due to thehyperphagia of ZF rats results in higher Srebp-1c expressionin ZF hepatocytes [45] The elevated SREBP-1c expressioncan further induceRaldh1 expression to create a feed-forwardmechanism that could be one of the reasons responsible forthe increased lipogenesis in the liver of ZF rats All of theseobservations indicate the potential roles of RA metabolismin the development of obesity and insulin resistance whichdeserves to be further studied

4 VArsquos Roles in Mediating Hepatic InsulinAction and Insulin Resistance

41 Insulin and Its Signal Transduction The insulin moleculeis made of two chains linked by one intra- and one interchaindisulfide bonds [235] The insulin receptor is a transmem-brane and heterotetramer tyrosine kinase receptor (two 120572and two 120573 subunits) linked by disulfide bonds as well [236]The binding of insulin to its receptor causes conformationchanges and transphosphorylation of the 120573-subunit tyrosinekinase [237 238] which initiates the signal transduction[239] Protein-protein interactions are involved in the trans-duction of insulin signalThe signal is transduced bymultiplecomponents in a complex network containing cascades ofkinases and phosphatases [240 241] The first intracellularcomponents mediating insulin signals are insulin recep-tor substrates (IRSs) protein molecules phosphorylated byinsulin receptor 120573-subunit and mediating insulin signals[242]

The insulin signal event is further amplified byphosphatidylinositide 3-kinases (PI3K)protein kinaseB (PKBAkt) pathway and GRB2mitogen-activated proteinkinase (MAPK) pathway [243ndash245] Another serinethre-onine kinase that can be activated by PI3K is the atypicalprotein kinase C [246] Human liver expresses severalprotein-tyrosine phosphatases (PTPs) [247] Okadai acid aninhibitor of protein phosphatase type 2A and type 1 inhibitsglycogen synthesis and insulin-stimulated Gck expression inprimary rat hepatocytes indicating that dephosphorylationmechanism may also participate in mediating insulinsignaling [248] These components are shared by insulin-likegrowth factor (IGF) receptor and involved in mediatinginsulin and IGF signals [249]

42 Metabolic Diseases and Insulin Resistance The rise ofthe number of people with one or more metabolic diseasessuch as obesity and diabetes in the world has become apublic health problem [250] The interactions of genetic andenvironmentalnutritional factors may be responsible for thecurrent rise of metabolic diseases The long evolutionaryprocess has equipped human and animal bodieswith a varietyof regulatory mechanisms controlling these interactions [251252] Human diets contain not only energy derived frommacronutrients but also micronutrients and other factors

which may influence the metabolic outcomes The roles ofindividual micronutrients in the development of metabolicdiseases are still unrevealed

One common property of human obesity and NIDDMis insulin resistance in which a given amount of insulinproduces less than normal physiological responses Dietaryfactors and manipulations have been considered to play arole in the development of insulin resistance in humans andanimals For example feeding an HFD to young and insulin-sensitive subjects for two days causes the development ofglucose intolerance [253] In the skeletal muscle of rats fedan HFD for 8 weeks the insulin-induced glucose uptakeis impaired [254] FFAs have been considered the factorsresponsible for HFD-induced leptin and insulin resistance[255ndash257]

43 Hepatic Insulin Resistance and Vicious Cycle The liverplays an essential role in the control of glucose andlipid homeostasis It coordinately regulates the processesin responses to nutritional and hormonal stimuli Insulinplays a major role in directing the liverrsquos metabolic status[258] which is partially attributed to the regulation of theexpression of genes involved in hepatic glucose and lipidmetabolism [215 259]

Insulin controls the expression of a variety of genesinvolved in glycolysis glycogenesis and lipogenesis andgluconeogenesis in the liver [145] Generally hepatic lipidand glucose metabolism is altered with the development ofinsulin resistance in obesity and NIDDM [258] This canbe reflected in the expression of insulin-regulated hepaticgenes for glucose and FA metabolism When the liver isinsulin sensitive insulin stimulates lipogenesis and inhibitsgluconeogenesis For example to regulate hepatic glucosehomeostasis insulin increases the expression of Gck gene[119 120] and Srebp-1c [224] a family member of SREBPswhich regulate the hepatic cholesterol and FA biosynthesisand their homeostasis [260] It suppresses the expressionof Pck1 [142] and G6pc [145] which control the first andlast steps of gluconeogenesis respectively When the liver isinsulin resistant insulin no longer inhibits gluconeogenesisHowever the liver still keeps the elevated lipogenesis Theelevated FA biosynthesis in the insulin-resistant state furtherfacilitates insulin secretion from pancreatic 120573-cells whichprobably enhances lipogenesis and results in a vicious cycle[113 261] The coexistence of the hepatic insulin resistanceand sensitivity at the gene expression level has been observedin rodent obese and diabetic models [215 258] Howeverthe mechanism of this coexistence of insulin sensitivity andresistance has not been revealed [261]

Recently the SREBP cleavage-activating protein gene(Scap) an escort protein necessary for generating nuclearforms of SREBPs has been knocked out in insulin-resistantobob mice [262] Deficiency of hepatic Scap reverses liverlipogenesis and steatosis in obobmice However the plasmalevels of glucose and insulin and the hepatic expression levelsof Pck1 andG6pcwere not different between the control obobmice and the obob mice with liver-specific Scap knockout[262] It seems that the suppression of hepatic FA synthesis

12 ISRN Hepatology

is not sufficient to correct insulin resistance Whether otherfactors play a role in the hepatic insulin resistance is still anopen question

The clinical use of RA-based medicine such asisotretinoin (13-cis RA) caused elevation of plasma TGlevels in human subjects [195ndash197] This increase in plasmaTG levels is also observed in rats [201ndash203] From our VAstatus studies we have shown that VA status affected theobesity development in ZF rats and reduced plasma insulinand TG levels in ZL and ZF rats suggesting improvement ofinsulin sensitivity [116] The hepatic expression of Srebp-1cwas reduced in VA-deficient animals [116] RA synergizeswith insulin to induce the expression of Srebp-1c in primaryrat hepatocytes [227] On the other hand RA treatmentinduces Pck1 expression and attenuates insulin-mediatedsuppression of its expression in primary rat hepatocytes [172]All of these observations demonstrate that RA attenuatesinsulin action (insulin-suppressed Pck1 expression) andstill promotes insulin action (insulin-induced Srebp-1cexpression) in the same primary hepatocytes

44 Possible Mechanism by Which RA Production Causes theDevelopment of the Vicious Cycle in Hepatocytes Could RAor other metabolites from VA catabolism be a factor thatcontributes to the hepatic insulin resistance and the viciouscycleUsing the regulation ofPck1 and Srebp-1c as themodel Ihave come upwith the following scheme to show that retinoidmetabolism could be a factor that causes the vicious cycle inthe liver As shown in Figure 3(a) in insulin-sensitive hepa-tocytes RA derived from retinal coordinates with insulin toregulate the expression of Srebp-1c and Pck1 The SREBP-1cprotein is processed to mature form a step that can be facili-tated by insulin [263] The mature form of SREBP-1c entersinto the nucleus and induces the mRNA levels of Raldh1and Fas which are respectively transcribed into RALDH1and FAS RALDH1 catalyzes the conversion of retinal to RAFAS catalyzes the synthesis of palmitate which is esterifiedinto TGs or elongated to longer FAs The Pck1 mRNA isused to translate into PEPCK-C protein which contributesto glucogenogenesis In the insulin-resistant hepatocytes asshown in Figure 3(b) the elevation of Raldh1 expressiondue to leptin deficiency [45] or induction of SREBP-1c byhigh-cholesterol feeding [232] induces the production of RAThe elevated RA levels will stimulate the transcription ofSrebp-1c and Pck1 This leads to more production of SREBP-1c and its mature form in the presence of higher insulinlevels in the insulin-resistant state The induction of SREBP-1c further enhances the transcription of Raldh1 and Fas andtheir corresponding proteins for the production of moreRAs and FAs respectively The RA production and SREBP-1c expression form a feed-forward cycle which causes moreTG and RA production in the insulin-resistant liver At thesame time more of the PEPCK-C protein is generated dueto the elevated Pck1 transcription by RA stimulation whichis not responsive to insulin inhibition as we have shown in[172] This leads to elevated gluconeogenesis in the insulin-resistant liver Eventually the phenotypes appear as if insulin

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1cRetinal

RALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(a) Insulin-sensitive hepatocytes

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1c

RetinalRALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(b) Insulin-resistant hepatocytes

Figure 3 The effects of RA on the insulin-regulated Srebp-1cand Pck1 expression levels the protein levels of SREBP-1c theexpression levels of Raldh1 and Fas and the fatty acid synthesisand gluconeogenesis in insulin-sensitive (a) and insulin-resistant (b)hepatocytes Please see the text in this paper for description Uparrows next to the text indicate induction The intensified weight ofthe lines indicates the induction of that part of the pathway

no longer suppresses gluconeogenesis while it still stimulatesFA synthesis in the insulin-resistant state

5 Perspectives and Future Directions

I have proposed a mechanism by which VA metabolismcontributes to the development of hepatic insulin resistanceIt explains some observations reported in the previous studiesof rodent obese and diabetic models [215 258] However itleavesmore open questionsThefirst one iswhat the initiationfactor is So far the elevated expression of Raldh1 mRNA inthe liver has been observed in ZF rats [45] and mice fed ahigh-cholesterol diet [232] These two conditions cause a lotof physiological changes such as overfeeding in ZF rats andchange of cholesterol biosynthesis in response to the feedingof high-cholesterol diet Knocking down Raldh1 specificallyin hepatocytes is needed to answer these questions The

ISRN Hepatology 13

second question is whether RA synthesis in hepatocytesis a regulated process in response to dietary or hormonalstimulations If Raldh1 is a downstream gene of SREBP-1cit should be regulated when the SREBP-1c level changes Asthe expression of Srebp-1c responds to insulin stimulation andoxysterols the regulation of Raldh1 expression in the livershould be studied The third question is why it is RALDH1but not other RALDHs Specific inhibitors of RALDHsmay be needed to answer this question Last question iswhether we can attenuate insulin resistance by suppressingthe RALDH1 activity in the liver It has been shown thatRaldh1minusminus mice are still insulin sensitive when they are onan HFD [26] This has been attributed to the effects on theadipogenesis However the liver of those knockout mice hasreduced lipid synthesis [231] Further studies are warrantedto answer all of these questions Hopefully it can become anintervention point for the treatment of insulin resistance andmetabolic diseases

Acknowledgments

This work was financially supported by a research grantfrom Allen Foundation Inc (to Guoxun Chen) a start-up fund from the University of Tennessee at Knoxville (toGuoxun Chen) and a Scientist Development Grant fromthe AmericanHeart Association (09SDG2140003 to GuoxunChen) The author thanks his colleague Dr Lauren Gellar forreading through this paper and offering her edits

References

[1] F G Hopkins ldquoFeeding experiments illustrating the impor-tance of accessory factors in normal dietariesrdquo The Journal ofPhysiology vol 44 no 5-6 pp 425ndash460 1912

[2] K J Carpenter ldquoA short history of nutritional science part 3(1912ndash1944)rdquo Journal of Nutrition vol 133 no 10 pp 3023ndash30322003

[3] E V McCollum and M Davis ldquoThe necessity of certain lipinsin the diet during growthrdquo Journal of Biological Chemistry vol15 no 1 pp 167ndash175 1913

[4] T B Osborne and L B Mendel ldquoFeeding experiments with fat-free food mixturesrdquo Journal of Biological Chemistry vol 12 no1 pp 81ndash89 1912

[5] R D Semba ldquoOn the lsquoDiscoveryrsquo of Vitamin Ardquo Annals ofNutrition and Metabolism vol 61 no 3 pp 192ndash198 2012

[6] R Blomhoff and H K Blomhoff ldquoOverview of retinoidmetabolism and functionrdquo Journal of Neurobiology vol 66 no7 pp 606ndash630 2006

[7] A Sommer ldquoVitamin A deficiency and clinical disease anhistorical overviewrdquo Journal of Nutrition vol 138 no 10 pp1835ndash1839 2008

[8] K J Rothman L L Moore M R Singer U-S Nguyen SMannino and A Milunsky ldquoTeratogenicity of high vitamin Aintakerdquo The New England Journal of Medicine vol 333 no 21pp 1369ndash1373 1995

[9] S Bershad A Rubinstein and J R Paterniti Jr ldquoChanges inplasma lipids and lipoproteins during isotretinoin therapy foracnerdquoThe New England Journal of Medicine vol 313 no 16 pp981ndash985 1985

[10] N Rodondi R Darioli A-A Ramelet et al ldquoHigh risk forhyperlipidemia and the metabolic syndrome after an episodeof hypertriglyceridemia during 13-cis retinoic acid therapy foracne a pharmacogenetic studyrdquo Annals of Internal Medicinevol 136 no 8 pp 582ndash589 2002

[11] H-U Klor A Weizel M Augustin et al ldquoThe impact oforal vitamin A derivatives on lipid metabolism what recom-mendations can be derived for dealing with this issue in thedaily dermatological practicerdquo Journal of the German Societyof Dermatology vol 9 no 8 pp 600ndash607 2011

[12] R M Russell ldquoThe vitamin A spectrum from deficiency totoxicityrdquoThe American Journal of Clinical Nutrition vol 71 no4 pp 878ndash884 2000

[13] A C Ross B Caballero R J Cousins K L Tucker and T RZiegler Modern Nutrition in Health and Diseases 11th edition2012

[14] E H Harrison ldquoMechanisms of digestion and absorption ofdietary vitamin Ardquo Annual Review of Nutrition vol 25 no 1pp 87ndash103 2005

[15] M R Lakshman ldquoAlpha and omega of carotenoid cleavagerdquoJournal of Nutrition vol 134 no 1 pp 241ndash245 2004

[16] I Potrykus ldquoNutritionally enhanced rice to combat malnutri-tion disorders of the poorrdquo Nutrition Reviews vol 61 no 6 ppS101ndashS104 2003

[17] A Wyss ldquoCarotene oxygenases a new family of double bondcleavage enzymesrdquo Journal of Nutrition vol 134 no 1 pp 246ndash250 2004

[18] R Kawaguchi J Yu J Honda et al ldquoA membrane receptor forretinol binding protein mediates cellular uptake of vitamin ArdquoScience vol 315 no 5813 pp 820ndash825 2007

[19] P Alapatt F Guo S M Komanetsky et al ldquoLiver retinoltransporter and receptor for serum retinol-binding protein(RBP4)rdquo Journal of Biological Chemistry vol 288 no 2 pp1250ndash1265 2013

[20] A R Moise N Noy K Palczewski and W S Blaner ldquoDeliveryof retinoid-based therapies to target tissuesrdquo Biochemistry vol46 no 15 pp 4449ndash4458 2007

[21] G Duester ldquoFamilies of retinoid dehydrogenases regulatingvitamin A function Production of visual pigment and retinoicacidrdquo European Journal of Biochemistry vol 267 no 14 pp4315ndash4324 2000

[22] M Theodosiou V Laudet and M Schubert ldquoFrom carrotto clinic an overview of the retinoic acid signaling pathwayrdquoCellular andMolecular Life Sciences vol 67 no 9 pp 1423ndash14452010

[23] J L Napoli ldquoInteractions of retinoid binding proteins andenzymes in retinoidmetabolismrdquoBiochimica et BiophysicaActavol 1440 no 2-3 pp 139ndash162 1999

[24] X Chai M H E M Boerman Y Zhai and J L NapolildquoCloning of a cDNA for liver microsomal retinol dehydro-genase A tissue-specific short-chain alcohol dehydrogenaserdquoJournal of Biological Chemistry vol 270 no 8 pp 3900ndash39041995

[25] B X Wu G Moiseyev Y Chen B Rohrer R K Crouch andJ-XMa ldquoIdentification of RDH10 an all-trans retinol dehydro-genase in retinal Muller cellsrdquo Investigative Ophthalmology andVisual Science vol 45 no 11 pp 3857ndash3862 2004

[26] O Ziouzenkova G Orasanu M Sharlach et al ldquoRetinalde-hyde represses adipogenesis and diet-induced obesityrdquo NatureMedicine vol 13 no 6 pp 695ndash702 2007

14 ISRN Hepatology

[27] J L Napoli ldquoPhysiological insights into all-trans-retinoic acidbiosynthesisrdquo Biochimica et Biophysica Acta vol 1821 no 1 pp152ndash167 2012

[28] G Wolf ldquoTissue-specific increases in endogenous all-transretinoic acid possible contributing factor in ethanol toxicityrdquoNutrition Reviews vol 68 no 11 pp 689ndash692 2010

[29] P V Bhat J Labrecque JM Boutin A Lacroix andA YoshidaldquoCloning of a cDNA encoding rat aldehyde dehydrogenase withhigh activity for retinal oxidationrdquoGene vol 166 no 2 pp 303ndash306 1995

[30] M Lin M Zhang M Abraham S M Smith and J LNapoli ldquoMouse retinal dehydrogenase 4 (RALDH4) molecularcloning cellular expression and activity in 9-cis-retinoic acidbiosynthesis in intact cellsrdquo Journal of Biological Chemistry vol278 no 11 pp 9856ndash9861 2003

[31] F A Mic A Molotkov X Fan A E Cuenca and GDuester ldquoRALDH3 a retinaldehyde dehydrogenase that gener-ates retinoic acid is expressed in the ventral retina otic vesicleand olfactory pit during mouse developmentrdquo Mechanisms ofDevelopment vol 97 no 1-2 pp 227ndash230 2000

[32] X Wang P Penzes and J L Napoli ldquoCloning of a cDNAencoding an aldehyde dehydrogenase and its expression inEscherichia coli recognition of retinal as substraterdquo Journal ofBiological Chemistry vol 271 no 27 pp 16288ndash16293 1996

[33] A Molotkov and G Duester ldquoGenetic evidence that retinalde-hyde dehydrogenase Raldh1 (Aldh1a1) functions downstreamof alcohol dehydrogenase Adh1 in metabolism of retinol toretinoic acidrdquo Journal of Biological Chemistry vol 278 no 38pp 36085ndash36090 2003

[34] G Elizondo J Corchero E Sterneck and F J GonzalezldquoFeedback inhibition of the retinaldehyde dehydrogenase geneALDH1 by retinoic acid through retinoic acid receptor 120572and CCAATenhancer-binding protein 120573rdquo Journal of BiologicalChemistry vol 275 no 50 pp 39747ndash39753 2000

[35] G Elizondo I M Medina-Dıaz R Cruz F J Gonzalez and LVega ldquoRetinoic acid modulates retinaldehyde dehydrogenase 1gene expression through the induction of GADD153-CEBP120573interactionrdquo Biochemical Pharmacology vol 77 no 2 pp 248ndash257 2009

[36] K Fujiwara M Kikuchi K Horiguchi et al ldquoEstrogen receptoralpha regulates retinaldehyde dehydrogenase 1 expression in ratanterior pituitary cellsrdquo Endocrine Journal vol 56 no 8 pp963ndash973 2009

[37] K Fujiwara F Maekawa M Kikuchi S Takigami T Yadaand T Yashiro ldquoExpression of retinaldehyde dehydrogenase(RALDH)2 and RALDH3 but not RALDH1 in the developinganterior pituitary glands of ratsrdquo Cell and Tissue Research vol328 no 1 pp 129ndash135 2007

[38] GWolf ldquoThe enzymatic cleavage of 120573-carotene still controver-sialrdquo Nutrition Reviews vol 53 no 5 pp 134ndash137 1995

[39] S Abu-Abed P Dolle D Metzger B Beckett P Chambonand M Petkovich ldquoThe retinoic acid-metabolizing enzymeCYP26A1 is essential for normal hindbrain patterning verte-bral identity and development of posterior structuresrdquo Genesand Development vol 15 no 2 pp 226ndash240 2001

[40] M A Leo S Iida and C S Lieber ldquoRetinoic acid metabolismby a system reconstituted with cytochrome P-450rdquo Archives ofBiochemistry and Biophysics vol 234 no 1 pp 305ndash312 1984

[41] MA Leo JM Lasker J L Raucy C-I KimM Black andC SLieber ldquoMetabolism of retinol and retinoic acid by human livercytochrome P450IIC8rdquoArchives of Biochemistry and Biophysicsvol 269 no 1 pp 305ndash312 1989

[42] R Quere A Baudet B Cassinat et al ldquoPharmacogenomicanalysis of acute promyelocytic leukemia cells highlightsCYP26cytochrome metabolism in differential all-trans retinoic acidsensitivityrdquo Blood vol 109 no 10 pp 4450ndash4460 2007

[43] J AWhite B Beckett-Jones Y-D Guo et al ldquocDNA cloning ofhuman retinoic acid-metabolizing enzyme (hP450RAI) identi-fies a novel family of cytochromes p450 (CYP26)rdquo Journal ofBiological Chemistry vol 272 no 30 pp 18538ndash18541 1997

[44] Y Zhang R Zolfaghari Reza and A C Ross ldquoMultiple retinoicacid response elements cooperate to enhance the inducibility ofCYP26A1 gene expression in liverrdquo Gene vol 464 no 1-2 pp32ndash43 2010

[45] Y Li Y Zhang R Li et al ldquoThe hepatic raldh1 expression iselevated in Zucker fatty rats and its over-expression introducedthe retinal-induced Srebp-1c expression in INS-1 cellsrdquo PLoSONE vol 7 no 9 Article ID e45210 2012

[46] R M Evans ldquoThe nuclear receptor superfamily a Rosetta stonefor physiologyrdquo Molecular Endocrinology vol 19 no 6 pp1429ndash1438 2005

[47] P Chambon ldquoA decade of molecular biology of retinoic acidreceptorsrdquo FASEB Journal vol 10 no 9 pp 940ndash954 1996

[48] D J Mangelsdorf and RM Evans ldquoThe RXR heterodimers andorphan receptorsrdquo Cell vol 83 no 6 pp 841ndash850 1995

[49] J E Balmer and R Blomhoff ldquoA robust characterization ofretinoic acid response elements based on a comparison of sitesin three speciesrdquo Journal of Steroid Biochemistry and MolecularBiology vol 96 no 5 pp 347ndash354 2005

[50] R Kurokawa J DiRenzo M Boehm et al ldquoRegulation ofretinoid signalling by receptor polarity and allosteric control ofligand bindingrdquo Nature vol 371 no 6497 pp 528ndash531 1994

[51] A Cvekl and W-L Wang ldquoRetinoic acid signaling in mam-malian eye developmentrdquo Experimental Eye Research vol 89no 3 pp 280ndash291 2009

[52] V Dupe M Davenne J Brocard et al ldquoIn vivo functional anal-ysis of the Hoxa-1 31015840 retinoic acid response element (31015840RARE)rdquoDevelopment vol 124 no 2 pp 399ndash410 1997

[53] A C Ross ldquoRetinoid production and catabolism role of dietin regulating retinol esterification and retinoic acid oxidationrdquoJournal of Nutrition vol 133 no 1 pp 291ndash296 2003

[54] T Moore and P D Holmes ldquoThe production of experimentalvitamin A deficiency in rats andmicerdquo Laboratory Animals vol5 no 2 pp 239ndash250 1971

[55] A C Ross and E H Harrison ldquoVitamin A and carotenoidsrdquoin Handbook of Vitamins D E McCormick R R Rucker J WSuttie et al Eds CRC Press Boca Raton Fla USA 4th edition2006

[56] A Chawta J J Repa R M Evans and D J MangelsdorfldquoNuclear receptors and lipid physiology opening the x-filesrdquoScience vol 294 no 5548 pp 1866ndash1870 2001

[57] C K Glass and M G Rosenfeld ldquoThe coregulator exchangein transcriptional functions of nuclear receptorsrdquo Genes andDevelopment vol 14 no 2 pp 121ndash141 2000

[58] A L Bookout Y Jeong M Downes R T Yu R M EvansandD JMangelsdorf ldquoAnatomical profiling of nuclear receptorexpression reveals a hierarchical transcriptional networkrdquo Cellvol 126 no 4 pp 789ndash799 2006

[59] B Mascrez M Mark W Krezel et al ldquoDifferential contribu-tions of AF-1 andAF-2 activities to the developmental functionsof RXR120572rdquo Development vol 128 no 11 pp 2049ndash2062 2001

[60] D Li T Li F Wang H Tian and H H Samuels ldquoFunctionalevidence for retinoid X receptor (RXR) as a nonsilent partner

ISRN Hepatology 15

in the thyroid hormone receptorRXR heterodimerrdquoMolecularand Cellular Biology vol 22 no 16 pp 5782ndash5792 2002

[61] F M Sladek W Zhong E Lai and J E Darnell Jr ldquoLiver-enriched transcription factor HNF-4 is a novel member ofthe steroid hormone receptor superfamilyrdquo Genes and Develop-ment vol 4 no 12 pp 2353ndash2365 1990

[62] K Yamagata H Furuta N Oda et al ldquoMutations in thehepatocyte nuclear factor-4120572 gene inmaturity-onset diabetes ofthe young (MODY1)rdquo Nature vol 384 no 6608 pp 458ndash4601996

[63] M Stoffel and S ADuncan ldquoThematurity-onset diabetes of theyoung (MODY1) transcription factor HNF4120572 regulates expres-sion of genes required for glucose transport and metabolismrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 24 pp 13209ndash13214 1997

[64] M Lehto P-O Bitzen B Isomaa et al ldquoMutation in the HNF-4120572 gene affects insulin secretion and triglyceride metabolismrdquoDiabetes vol 48 no 2 pp 423ndash425 1999

[65] G P Hayhurst Y-H Lee G Lambert J M Ward and F JGonzalez ldquoHepatocyte nuclear factor 4120572 (Nuclear receptor 2A1)is essential formaintenance of hepatic gene expression and lipidhomeostasisrdquo Molecular and Cellular Biology vol 21 no 4 pp1393ndash1403 2001

[66] U Roth K Jungermann and T Kietzmann ldquoActivation ofglucokinase gene expression by hepatic nuclear factor 4120572 inprimary hepatocytesrdquo Biochemical Journal vol 365 no 1 pp223ndash228 2002

[67] S Mandard R Stienstra P Escher et al ldquoGlycogen synthase2 is a novel target gene of peroxisome proliferator-activatedreceptorsrdquo Cellular and Molecular Life Sciences vol 64 no 9pp 1145ndash1157 2007

[68] F Rajas A Gautier I Bady S Montano and G MithieuxldquoPolyunsaturated fatty acyl coenzyme a suppress the glucose-6-phosphatase promoter activity bymodulating the DNA bindingof hepatocyte nuclear factor 4120572rdquo Journal of Biological Chemistryvol 277 no 18 pp 15736ndash15744 2002

[69] B Viollet A Kahn and M Raymondjean ldquoProtein kinase A-dependent phosphorylation modulates DNA-binding activityof hepatocyte nuclear factor 4rdquoMolecular and Cellular Biologyvol 17 no 8 pp 4208ndash4219 1997

[70] L Palanker J M Tennessen G Lam and C S Thum-mel ldquoDrosophila HNF4 regulates lipid mobilization and 120573-oxidationrdquo Cell Metabolism vol 9 no 3 pp 228ndash239 2009

[71] A Miura K Yamagata M Kakei et al ldquoHepatocyte nuclearfactor-4120572 is essential for glucose-stimulated insulin secretion bypancreatic 120573-cellsrdquo Journal of Biological Chemistry vol 281 no8 pp 5246ndash5257 2006

[72] R Bartoov-Shifman R Hertz H Wang C B Wollheim JBar-Tana and M D Walker ldquoActivation of the insulin genepromoter through a direct effect of hepatocyte nuclear factor4120572rdquo Journal of Biological Chemistry vol 277 no 29 pp 25914ndash25919 2002

[73] H Wang P Maechler P A Antinozzi K A Hagenfeldt andC B Wollheim ldquoHepatocyte nuclear factor 4120572 regulates theexpression of pancreatic 120573-cell genes implicated in glucosemetabolism and nutrient-induced insulin secretionrdquo Journal ofBiological Chemistry vol 275 no 46 pp 35953ndash35959 2000

[74] K Reue T Leff and J L Breslow ldquoHuman apolipoproteinCIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factorsrdquo Journal ofBiological Chemistry vol 263 no 14 pp 6857ndash6864 1988

[75] T Leff K Reue A Melian H Culver and J L BreslowldquoA regulatory element in the apoCIII promoter that directshepatic specific transcription binds to proteins in expressingand nonexpressing cell typesrdquo Journal of Biological Chemistryvol 264 no 27 pp 16132ndash16137 1989

[76] S N Lavrentiadou M Hadzopoulou-Cladaras D Kardassisand V I Zannis ldquoBinding specificity and modulation of thehuman apocIII promoter activity by heterodimers of ligand-dependent nuclear receptorsrdquo Biochemistry vol 38 no 3 pp964ndash975 1999

[77] T R Magee Y Cai M E El-Houseini J Locker and Y-JY Wan ldquoRetinoic acid mediates down-regulation of the 120572-fetoprotein gene through decreased expression of hepatocytenuclear factorsrdquo Journal of Biological Chemistry vol 273 no 45pp 30024ndash30032 1998

[78] A Qian Y Cai T R Magee and Y J Y Wan ldquoIdentificationof retinoic acid-responsive elements on the HNF1alpha andHNF4alpha genesrdquo Biochemical and Biophysical Research Com-munications vol 276 no 3 pp 837ndash842 2000

[79] H Nakshatri and P Chambon ldquoThe directly repeatedRG(GT)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites forRAR RXR HNF-4 and ARP-1 homo- and heterodimersrdquoJournal of Biological Chemistry vol 269 no 2 pp 890ndash9021994

[80] T Makita G Hernandez-Hoyos T H-P Chen H Wu E VRothenberg and H M Sucov ldquoA developmental transition indefinitive erythropoiesis erythropoietin expression is sequen-tially regulated by retinoic acid receptors andHNF4rdquoGenes andDevelopment vol 15 no 7 pp 889ndash901 2001

[81] T I Kambe J Tada-Kambe Y Kuge Y Yamaguchi-Iwai MNagao and R Sasaki ldquoRetinoic acid stimulates erythropoietingene transcription in embryonal carcinoma cells through thedirect repeat of a steroidthyroid hormone receptor responseelement half-site in the hypoxia-response enhancerrdquo Blood vol96 no 9 pp 3265ndash3271 2000

[82] F-J Lin J Qin K Tang S Y Tsai and M-J Tsai ldquoCoup drsquoEtatan orphan takes controlrdquo Endocrine Reviews vol 32 no 3 pp404ndash421 2011

[83] L-H Wang S Y Tsai R G Cook W G Beattie M-J Tsaiand BW OrsquoMalley ldquoCOUP transcription factor is a member ofthe steroid receptor superfamilyrdquoNature vol 340 no 6229 pp163ndash166 1989

[84] X Leng A J Cooney S Y Tsai and M-J Tsai ldquoMolecularmechanisms of COUP-TF-mediated transcriptional repressionevidence for transrepression and active repressionrdquo Molecularand Cellular Biology vol 16 no 5 pp 2332ndash2340 1996

[85] L Li X Xie J Qin et al ldquoThe nuclear orphan receptorCOUP-TFII plays an essential role in adipogenesis glucosehomeostasis and energy metabolismrdquo Cell Metabolism vol 9no 1 pp 77ndash87 2009

[86] F A Pereira Q Yuhong G Zhou M-J Tsai and S YTsai ldquoThe orphan nuclear receptor COUP-TFII is required forangiogenesis and heart developmentrdquo Genes and Developmentvol 13 no 8 pp 1037ndash1049 1999

[87] N Takamoto I Kurihara K Lee F J DeMayo M-J Tsai andS Y Tsai ldquoHaploinsufficiency of chicken ovalbumin upstreampromoter transcription factor II in female reproductionrdquoMolec-ular Endocrinology vol 19 no 9 pp 2299ndash2308 2005

[88] P Zhang M Bennoun C Gogard et al ldquoExpression of COUP-TFII in metabolic tissues during developmentrdquo Mechanisms ofDevelopment vol 119 no 1 pp 109ndash114 2002

16 ISRN Hepatology

[89] Z Xu S Yu C-H Hsu J Eguchi and E D Rosen ldquoTheorphan nuclear receptor chicken ovalbumin upstream pro-moter-transcription factor II is a critical regulator of adipogene-sisrdquoProceedings of theNationalAcademy of Sciences of theUnitedStates of America vol 105 no 7 pp 2421ndash2426 2008

[90] P Bardoux P Zhang D Flamez et al ldquoEssential role of chickenovalbumin upstreampromoter-transcription factor II in insulinsecretion and insulin sensitivity revealed by conditional geneknockoutrdquo Diabetes vol 54 no 5 pp 1357ndash1363 2005

[91] G Achatz B Holzl R Speckmayer C Hauser F Sandhoferand B Paulweber ldquoFunctional domains of the human orphanreceptor ARP-1COUP-TFII involved in active repression andtransrepressionrdquo Molecular and Cellular Biology vol 17 no 9pp 4914ndash4932 1997

[92] S A Kliewer K Umesono R A Heyman D J MangelsdorfJ A Dyck and R M Evans ldquoRetinoid X receptor-COUP-TFinteractionsmodulate retinoic acid signalingrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol89 no 4 pp 1448ndash1452 1992

[93] A J Cooney S Y Tsai BW OrsquoMalley andM-J Tsai ldquoChickenovalbumin upstreampromoter transcription factor (COUP-TF)dimers bind to different GGTCA response elements allowingCOUP-TF to repress hormonal induction of the vitamin D3thyroid hormone and retinoic acid receptorsrdquo Molecular andCellular Biology vol 12 no 9 pp 4153ndash4163 1992

[94] SW Kruse K Suino-Powell X E Zhou et al ldquoIdentification ofCOUP-TFII orphannuclear receptor as a retinoic acid-activatedreceptorrdquo PLoS Biology vol 6 no 9 Article ID e227 2008

[95] J P Berger T E Akiyama and P T Meinke ldquoPPARs thera-peutic targets for metabolic diseaserdquo Trends in PharmacologicalSciences vol 26 no 5 pp 244ndash251 2005

[96] JM Peters andF J Gonzalez ldquoSorting out the functional role(s)of peroxisome proliferator-activated receptor-120573120575 (PPAR120573120575)in cell proliferation and cancerrdquo Biochimica et Biophysica Actavol 1796 no 2 pp 230ndash241 2009

[97] A Tenenbaum and E Fisman ldquoBalanced pan-PPAR activatorbezafibrate in combination with statin comprehensive lipidscontrol and diabetes preventionrdquo Cardiovascular Diabetologyvol 11 no 1 article 140 2012

[98] O Braissant F Foufelle C Scotto M Dauca and W WahlildquoDifferential expression of peroxisome proliferator-activatedreceptors (PPARs) tissue distribution of PPAR-120572 -120573 and -120574 inthe adult ratrdquo Endocrinology vol 137 no 1 pp 354ndash366 1996

[99] H Higashiyama A N Billin Y Okamoto M Kinoshita andS Asano ldquoExpression profiling of Peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues usingtissue microarrayrdquo Histochemistry and Cell Biology vol 127 no5 pp 485ndash494 2007

[100] P S Jones R Savory P Barratt et al ldquoChromosomal local-isation inducibility tissue-specific expression and strain dif-ferences in three murine peroxisome-proliferator-activated-receptor genesrdquo European Journal of Biochemistry vol 233 no1 pp 219ndash226 1995

[101] S A Kliewer B M Forman B Blumberg et al ldquoDifferentialexpression and activation of a family of murine peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no15 pp 7355ndash7359 1994

[102] E E Girroir H E Hollingshead P He B Zhu G H Perdewand J M Peters ldquoQuantitative expression patterns of peroxi-some proliferator-activated receptor-120573120575 (PPAR120573120575) protein in

micerdquo Biochemical and Biophysical Research Communicationsvol 371 no 3 pp 456ndash461 2008

[103] P Escher O Braissant S Basu-Modak L Michalik W Wahliand B Desvergne ldquoRat PPARs quantitative analysis in adult rattissues and regulation in fasting and refeedingrdquo Endocrinologyvol 142 no 10 pp 4195ndash4202 2001

[104] D Auboeuf J Rieusset L Fajas et al ldquoTissue distributionand quantification of the expression of mRNAs of peroxi-some proliferator-activated receptors and liver X receptor-120572 inhumans no alteration in adipose tissue of obese and NIDDMpatientsrdquo Diabetes vol 46 no 8 pp 1319ndash1327 1997

[105] N ShawM Elholm andN Noy ldquoRetinoic acid is a high affinityselective ligand for the peroxisome proliferator-activated recep-tor 120573120575rdquo Journal of Biological Chemistry vol 278 no 43 pp41589ndash41592 2003

[106] G Wolf ldquoRetinoic acid as cause of cell proliferation or cellgrowth inhibition depending on activation of one of twodifferent nuclear receptorsrdquoNutrition Reviews vol 66 no 1 pp55ndash59 2008

[107] T T Schug D C Berry N S Shaw S N Travis and N NoyldquoOpposing effects of retinoic acid on cell growth result fromalternate activation of two different nuclear receptorsrdquo Cell vol129 no 4 pp 723ndash733 2007

[108] D C Berry and N Noy ldquoAll-trans-retinoic acid repressesobesity and insulin resistance by activating both peroxisomeproliferation-activated receptor 120573120575 and retinoic acid receptorrdquoMolecular and Cellular Biology vol 29 no 12 pp 3286ndash32962009

[109] D C Berry D DeSantis H Soltanian C M Croniger andN Noy ldquoRetinoic acid upregulates preadipocyte genes to blockadipogenesis and suppress diet-induced obesityrdquo Diabetes vol61 no 5 pp 1112ndash1121 2012

[110] M G Borland C Khozoie P P Albrecht et al ldquoStableover-expression of PPAR120573120575 and PPAR120574 to examine receptorsignaling in human HaCaT keratinocytesrdquo Cellular Signallingvol 23 no 12 pp 2039ndash2050 2011

[111] S E OrsquoSullivan and D A Kendall ldquoCannabinoid activationof peroxisome proliferator-activated receptors potential formodulation of inflammatory diseaserdquo Immunobiology vol 215no 8 pp 611ndash616 2010

[112] Z C Yan D Y Liu L L Zhang et al ldquoExercise reduces adiposetissue via cannabinoid receptor type 1 which is regulated byperoxisome proliferator-activated receptor-120575rdquo Biochemical andBiophysical Research Communications vol 354 no 2 pp 427ndash433 2007

[113] J D McGarry ldquoWhat if Minkowski had been ageusic Analternative angle on diabetesrdquo Science vol 258 no 5083 pp766ndash770 1992

[114] TMoore ldquoVitaminA and carotene the vitaminA reserve of theadult human being in health and diseaserdquo Biochemical Journalvol 31 no 1 pp 155ndash164 1937

[115] GWolfMD Lane and B C Johnson ldquoStudies on the functionof vitamin A in metabolismrdquo Journal of Biological Chemistryvol 225 no 2 pp 995ndash1008 1957

[116] Y Zhang R Li Y Li W Chen S Zhao and G Chen ldquoVitaminA status affects obesity development and hepatic expression ofkey genes for fuel metabolism in Zucker fatty ratsrdquoBiochemistryand Cell Biology vol 90 no 4 pp 548ndash557 2012

[117] M Singh V N Singh and T A Venkitasubramanian ldquoEarlyeffects of feeding excess vitamin A hepatic glycogen bloodlactic acid plasma nefa and glucose tolerance in ratsrdquo LifeSciences vol 7 no 5 pp 239ndash247 1968

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

12 ISRN Hepatology

is not sufficient to correct insulin resistance Whether otherfactors play a role in the hepatic insulin resistance is still anopen question

The clinical use of RA-based medicine such asisotretinoin (13-cis RA) caused elevation of plasma TGlevels in human subjects [195ndash197] This increase in plasmaTG levels is also observed in rats [201ndash203] From our VAstatus studies we have shown that VA status affected theobesity development in ZF rats and reduced plasma insulinand TG levels in ZL and ZF rats suggesting improvement ofinsulin sensitivity [116] The hepatic expression of Srebp-1cwas reduced in VA-deficient animals [116] RA synergizeswith insulin to induce the expression of Srebp-1c in primaryrat hepatocytes [227] On the other hand RA treatmentinduces Pck1 expression and attenuates insulin-mediatedsuppression of its expression in primary rat hepatocytes [172]All of these observations demonstrate that RA attenuatesinsulin action (insulin-suppressed Pck1 expression) andstill promotes insulin action (insulin-induced Srebp-1cexpression) in the same primary hepatocytes

44 Possible Mechanism by Which RA Production Causes theDevelopment of the Vicious Cycle in Hepatocytes Could RAor other metabolites from VA catabolism be a factor thatcontributes to the hepatic insulin resistance and the viciouscycleUsing the regulation ofPck1 and Srebp-1c as themodel Ihave come upwith the following scheme to show that retinoidmetabolism could be a factor that causes the vicious cycle inthe liver As shown in Figure 3(a) in insulin-sensitive hepa-tocytes RA derived from retinal coordinates with insulin toregulate the expression of Srebp-1c and Pck1 The SREBP-1cprotein is processed to mature form a step that can be facili-tated by insulin [263] The mature form of SREBP-1c entersinto the nucleus and induces the mRNA levels of Raldh1and Fas which are respectively transcribed into RALDH1and FAS RALDH1 catalyzes the conversion of retinal to RAFAS catalyzes the synthesis of palmitate which is esterifiedinto TGs or elongated to longer FAs The Pck1 mRNA isused to translate into PEPCK-C protein which contributesto glucogenogenesis In the insulin-resistant hepatocytes asshown in Figure 3(b) the elevation of Raldh1 expressiondue to leptin deficiency [45] or induction of SREBP-1c byhigh-cholesterol feeding [232] induces the production of RAThe elevated RA levels will stimulate the transcription ofSrebp-1c and Pck1 This leads to more production of SREBP-1c and its mature form in the presence of higher insulinlevels in the insulin-resistant state The induction of SREBP-1c further enhances the transcription of Raldh1 and Fas andtheir corresponding proteins for the production of moreRAs and FAs respectively The RA production and SREBP-1c expression form a feed-forward cycle which causes moreTG and RA production in the insulin-resistant liver At thesame time more of the PEPCK-C protein is generated dueto the elevated Pck1 transcription by RA stimulation whichis not responsive to insulin inhibition as we have shown in[172] This leads to elevated gluconeogenesis in the insulin-resistant liver Eventually the phenotypes appear as if insulin

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1cRetinal

RALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(a) Insulin-sensitive hepatocytes

NucleusCell membrane

Retinol

RDHs

FASFATG

SRE

SRE

FasmRNA Mature

SREBP-1c

RetinalRALDH1

RA

RA

CytosolNuclear

membrane

21

21PEPCK-C

Insulin

mRNARaldh1

Pck1mRNA

RAREs

LXREsRAREsInduction

Induction

Induction

InhibitionSignal

cascade

Gluconeogenesis

SREBP-1c

mRNASrebp-1c

(b) Insulin-resistant hepatocytes

Figure 3 The effects of RA on the insulin-regulated Srebp-1cand Pck1 expression levels the protein levels of SREBP-1c theexpression levels of Raldh1 and Fas and the fatty acid synthesisand gluconeogenesis in insulin-sensitive (a) and insulin-resistant (b)hepatocytes Please see the text in this paper for description Uparrows next to the text indicate induction The intensified weight ofthe lines indicates the induction of that part of the pathway

no longer suppresses gluconeogenesis while it still stimulatesFA synthesis in the insulin-resistant state

5 Perspectives and Future Directions

I have proposed a mechanism by which VA metabolismcontributes to the development of hepatic insulin resistanceIt explains some observations reported in the previous studiesof rodent obese and diabetic models [215 258] However itleavesmore open questionsThefirst one iswhat the initiationfactor is So far the elevated expression of Raldh1 mRNA inthe liver has been observed in ZF rats [45] and mice fed ahigh-cholesterol diet [232] These two conditions cause a lotof physiological changes such as overfeeding in ZF rats andchange of cholesterol biosynthesis in response to the feedingof high-cholesterol diet Knocking down Raldh1 specificallyin hepatocytes is needed to answer these questions The

ISRN Hepatology 13

second question is whether RA synthesis in hepatocytesis a regulated process in response to dietary or hormonalstimulations If Raldh1 is a downstream gene of SREBP-1cit should be regulated when the SREBP-1c level changes Asthe expression of Srebp-1c responds to insulin stimulation andoxysterols the regulation of Raldh1 expression in the livershould be studied The third question is why it is RALDH1but not other RALDHs Specific inhibitors of RALDHsmay be needed to answer this question Last question iswhether we can attenuate insulin resistance by suppressingthe RALDH1 activity in the liver It has been shown thatRaldh1minusminus mice are still insulin sensitive when they are onan HFD [26] This has been attributed to the effects on theadipogenesis However the liver of those knockout mice hasreduced lipid synthesis [231] Further studies are warrantedto answer all of these questions Hopefully it can become anintervention point for the treatment of insulin resistance andmetabolic diseases

Acknowledgments

This work was financially supported by a research grantfrom Allen Foundation Inc (to Guoxun Chen) a start-up fund from the University of Tennessee at Knoxville (toGuoxun Chen) and a Scientist Development Grant fromthe AmericanHeart Association (09SDG2140003 to GuoxunChen) The author thanks his colleague Dr Lauren Gellar forreading through this paper and offering her edits

References

[1] F G Hopkins ldquoFeeding experiments illustrating the impor-tance of accessory factors in normal dietariesrdquo The Journal ofPhysiology vol 44 no 5-6 pp 425ndash460 1912

[2] K J Carpenter ldquoA short history of nutritional science part 3(1912ndash1944)rdquo Journal of Nutrition vol 133 no 10 pp 3023ndash30322003

[3] E V McCollum and M Davis ldquoThe necessity of certain lipinsin the diet during growthrdquo Journal of Biological Chemistry vol15 no 1 pp 167ndash175 1913

[4] T B Osborne and L B Mendel ldquoFeeding experiments with fat-free food mixturesrdquo Journal of Biological Chemistry vol 12 no1 pp 81ndash89 1912

[5] R D Semba ldquoOn the lsquoDiscoveryrsquo of Vitamin Ardquo Annals ofNutrition and Metabolism vol 61 no 3 pp 192ndash198 2012

[6] R Blomhoff and H K Blomhoff ldquoOverview of retinoidmetabolism and functionrdquo Journal of Neurobiology vol 66 no7 pp 606ndash630 2006

[7] A Sommer ldquoVitamin A deficiency and clinical disease anhistorical overviewrdquo Journal of Nutrition vol 138 no 10 pp1835ndash1839 2008

[8] K J Rothman L L Moore M R Singer U-S Nguyen SMannino and A Milunsky ldquoTeratogenicity of high vitamin Aintakerdquo The New England Journal of Medicine vol 333 no 21pp 1369ndash1373 1995

[9] S Bershad A Rubinstein and J R Paterniti Jr ldquoChanges inplasma lipids and lipoproteins during isotretinoin therapy foracnerdquoThe New England Journal of Medicine vol 313 no 16 pp981ndash985 1985

[10] N Rodondi R Darioli A-A Ramelet et al ldquoHigh risk forhyperlipidemia and the metabolic syndrome after an episodeof hypertriglyceridemia during 13-cis retinoic acid therapy foracne a pharmacogenetic studyrdquo Annals of Internal Medicinevol 136 no 8 pp 582ndash589 2002

[11] H-U Klor A Weizel M Augustin et al ldquoThe impact oforal vitamin A derivatives on lipid metabolism what recom-mendations can be derived for dealing with this issue in thedaily dermatological practicerdquo Journal of the German Societyof Dermatology vol 9 no 8 pp 600ndash607 2011

[12] R M Russell ldquoThe vitamin A spectrum from deficiency totoxicityrdquoThe American Journal of Clinical Nutrition vol 71 no4 pp 878ndash884 2000

[13] A C Ross B Caballero R J Cousins K L Tucker and T RZiegler Modern Nutrition in Health and Diseases 11th edition2012

[14] E H Harrison ldquoMechanisms of digestion and absorption ofdietary vitamin Ardquo Annual Review of Nutrition vol 25 no 1pp 87ndash103 2005

[15] M R Lakshman ldquoAlpha and omega of carotenoid cleavagerdquoJournal of Nutrition vol 134 no 1 pp 241ndash245 2004

[16] I Potrykus ldquoNutritionally enhanced rice to combat malnutri-tion disorders of the poorrdquo Nutrition Reviews vol 61 no 6 ppS101ndashS104 2003

[17] A Wyss ldquoCarotene oxygenases a new family of double bondcleavage enzymesrdquo Journal of Nutrition vol 134 no 1 pp 246ndash250 2004

[18] R Kawaguchi J Yu J Honda et al ldquoA membrane receptor forretinol binding protein mediates cellular uptake of vitamin ArdquoScience vol 315 no 5813 pp 820ndash825 2007

[19] P Alapatt F Guo S M Komanetsky et al ldquoLiver retinoltransporter and receptor for serum retinol-binding protein(RBP4)rdquo Journal of Biological Chemistry vol 288 no 2 pp1250ndash1265 2013

[20] A R Moise N Noy K Palczewski and W S Blaner ldquoDeliveryof retinoid-based therapies to target tissuesrdquo Biochemistry vol46 no 15 pp 4449ndash4458 2007

[21] G Duester ldquoFamilies of retinoid dehydrogenases regulatingvitamin A function Production of visual pigment and retinoicacidrdquo European Journal of Biochemistry vol 267 no 14 pp4315ndash4324 2000

[22] M Theodosiou V Laudet and M Schubert ldquoFrom carrotto clinic an overview of the retinoic acid signaling pathwayrdquoCellular andMolecular Life Sciences vol 67 no 9 pp 1423ndash14452010

[23] J L Napoli ldquoInteractions of retinoid binding proteins andenzymes in retinoidmetabolismrdquoBiochimica et BiophysicaActavol 1440 no 2-3 pp 139ndash162 1999

[24] X Chai M H E M Boerman Y Zhai and J L NapolildquoCloning of a cDNA for liver microsomal retinol dehydro-genase A tissue-specific short-chain alcohol dehydrogenaserdquoJournal of Biological Chemistry vol 270 no 8 pp 3900ndash39041995

[25] B X Wu G Moiseyev Y Chen B Rohrer R K Crouch andJ-XMa ldquoIdentification of RDH10 an all-trans retinol dehydro-genase in retinal Muller cellsrdquo Investigative Ophthalmology andVisual Science vol 45 no 11 pp 3857ndash3862 2004

[26] O Ziouzenkova G Orasanu M Sharlach et al ldquoRetinalde-hyde represses adipogenesis and diet-induced obesityrdquo NatureMedicine vol 13 no 6 pp 695ndash702 2007

14 ISRN Hepatology

[27] J L Napoli ldquoPhysiological insights into all-trans-retinoic acidbiosynthesisrdquo Biochimica et Biophysica Acta vol 1821 no 1 pp152ndash167 2012

[28] G Wolf ldquoTissue-specific increases in endogenous all-transretinoic acid possible contributing factor in ethanol toxicityrdquoNutrition Reviews vol 68 no 11 pp 689ndash692 2010

[29] P V Bhat J Labrecque JM Boutin A Lacroix andA YoshidaldquoCloning of a cDNA encoding rat aldehyde dehydrogenase withhigh activity for retinal oxidationrdquoGene vol 166 no 2 pp 303ndash306 1995

[30] M Lin M Zhang M Abraham S M Smith and J LNapoli ldquoMouse retinal dehydrogenase 4 (RALDH4) molecularcloning cellular expression and activity in 9-cis-retinoic acidbiosynthesis in intact cellsrdquo Journal of Biological Chemistry vol278 no 11 pp 9856ndash9861 2003

[31] F A Mic A Molotkov X Fan A E Cuenca and GDuester ldquoRALDH3 a retinaldehyde dehydrogenase that gener-ates retinoic acid is expressed in the ventral retina otic vesicleand olfactory pit during mouse developmentrdquo Mechanisms ofDevelopment vol 97 no 1-2 pp 227ndash230 2000

[32] X Wang P Penzes and J L Napoli ldquoCloning of a cDNAencoding an aldehyde dehydrogenase and its expression inEscherichia coli recognition of retinal as substraterdquo Journal ofBiological Chemistry vol 271 no 27 pp 16288ndash16293 1996

[33] A Molotkov and G Duester ldquoGenetic evidence that retinalde-hyde dehydrogenase Raldh1 (Aldh1a1) functions downstreamof alcohol dehydrogenase Adh1 in metabolism of retinol toretinoic acidrdquo Journal of Biological Chemistry vol 278 no 38pp 36085ndash36090 2003

[34] G Elizondo J Corchero E Sterneck and F J GonzalezldquoFeedback inhibition of the retinaldehyde dehydrogenase geneALDH1 by retinoic acid through retinoic acid receptor 120572and CCAATenhancer-binding protein 120573rdquo Journal of BiologicalChemistry vol 275 no 50 pp 39747ndash39753 2000

[35] G Elizondo I M Medina-Dıaz R Cruz F J Gonzalez and LVega ldquoRetinoic acid modulates retinaldehyde dehydrogenase 1gene expression through the induction of GADD153-CEBP120573interactionrdquo Biochemical Pharmacology vol 77 no 2 pp 248ndash257 2009

[36] K Fujiwara M Kikuchi K Horiguchi et al ldquoEstrogen receptoralpha regulates retinaldehyde dehydrogenase 1 expression in ratanterior pituitary cellsrdquo Endocrine Journal vol 56 no 8 pp963ndash973 2009

[37] K Fujiwara F Maekawa M Kikuchi S Takigami T Yadaand T Yashiro ldquoExpression of retinaldehyde dehydrogenase(RALDH)2 and RALDH3 but not RALDH1 in the developinganterior pituitary glands of ratsrdquo Cell and Tissue Research vol328 no 1 pp 129ndash135 2007

[38] GWolf ldquoThe enzymatic cleavage of 120573-carotene still controver-sialrdquo Nutrition Reviews vol 53 no 5 pp 134ndash137 1995

[39] S Abu-Abed P Dolle D Metzger B Beckett P Chambonand M Petkovich ldquoThe retinoic acid-metabolizing enzymeCYP26A1 is essential for normal hindbrain patterning verte-bral identity and development of posterior structuresrdquo Genesand Development vol 15 no 2 pp 226ndash240 2001

[40] M A Leo S Iida and C S Lieber ldquoRetinoic acid metabolismby a system reconstituted with cytochrome P-450rdquo Archives ofBiochemistry and Biophysics vol 234 no 1 pp 305ndash312 1984

[41] MA Leo JM Lasker J L Raucy C-I KimM Black andC SLieber ldquoMetabolism of retinol and retinoic acid by human livercytochrome P450IIC8rdquoArchives of Biochemistry and Biophysicsvol 269 no 1 pp 305ndash312 1989

[42] R Quere A Baudet B Cassinat et al ldquoPharmacogenomicanalysis of acute promyelocytic leukemia cells highlightsCYP26cytochrome metabolism in differential all-trans retinoic acidsensitivityrdquo Blood vol 109 no 10 pp 4450ndash4460 2007

[43] J AWhite B Beckett-Jones Y-D Guo et al ldquocDNA cloning ofhuman retinoic acid-metabolizing enzyme (hP450RAI) identi-fies a novel family of cytochromes p450 (CYP26)rdquo Journal ofBiological Chemistry vol 272 no 30 pp 18538ndash18541 1997

[44] Y Zhang R Zolfaghari Reza and A C Ross ldquoMultiple retinoicacid response elements cooperate to enhance the inducibility ofCYP26A1 gene expression in liverrdquo Gene vol 464 no 1-2 pp32ndash43 2010

[45] Y Li Y Zhang R Li et al ldquoThe hepatic raldh1 expression iselevated in Zucker fatty rats and its over-expression introducedthe retinal-induced Srebp-1c expression in INS-1 cellsrdquo PLoSONE vol 7 no 9 Article ID e45210 2012

[46] R M Evans ldquoThe nuclear receptor superfamily a Rosetta stonefor physiologyrdquo Molecular Endocrinology vol 19 no 6 pp1429ndash1438 2005

[47] P Chambon ldquoA decade of molecular biology of retinoic acidreceptorsrdquo FASEB Journal vol 10 no 9 pp 940ndash954 1996

[48] D J Mangelsdorf and RM Evans ldquoThe RXR heterodimers andorphan receptorsrdquo Cell vol 83 no 6 pp 841ndash850 1995

[49] J E Balmer and R Blomhoff ldquoA robust characterization ofretinoic acid response elements based on a comparison of sitesin three speciesrdquo Journal of Steroid Biochemistry and MolecularBiology vol 96 no 5 pp 347ndash354 2005

[50] R Kurokawa J DiRenzo M Boehm et al ldquoRegulation ofretinoid signalling by receptor polarity and allosteric control ofligand bindingrdquo Nature vol 371 no 6497 pp 528ndash531 1994

[51] A Cvekl and W-L Wang ldquoRetinoic acid signaling in mam-malian eye developmentrdquo Experimental Eye Research vol 89no 3 pp 280ndash291 2009

[52] V Dupe M Davenne J Brocard et al ldquoIn vivo functional anal-ysis of the Hoxa-1 31015840 retinoic acid response element (31015840RARE)rdquoDevelopment vol 124 no 2 pp 399ndash410 1997

[53] A C Ross ldquoRetinoid production and catabolism role of dietin regulating retinol esterification and retinoic acid oxidationrdquoJournal of Nutrition vol 133 no 1 pp 291ndash296 2003

[54] T Moore and P D Holmes ldquoThe production of experimentalvitamin A deficiency in rats andmicerdquo Laboratory Animals vol5 no 2 pp 239ndash250 1971

[55] A C Ross and E H Harrison ldquoVitamin A and carotenoidsrdquoin Handbook of Vitamins D E McCormick R R Rucker J WSuttie et al Eds CRC Press Boca Raton Fla USA 4th edition2006

[56] A Chawta J J Repa R M Evans and D J MangelsdorfldquoNuclear receptors and lipid physiology opening the x-filesrdquoScience vol 294 no 5548 pp 1866ndash1870 2001

[57] C K Glass and M G Rosenfeld ldquoThe coregulator exchangein transcriptional functions of nuclear receptorsrdquo Genes andDevelopment vol 14 no 2 pp 121ndash141 2000

[58] A L Bookout Y Jeong M Downes R T Yu R M EvansandD JMangelsdorf ldquoAnatomical profiling of nuclear receptorexpression reveals a hierarchical transcriptional networkrdquo Cellvol 126 no 4 pp 789ndash799 2006

[59] B Mascrez M Mark W Krezel et al ldquoDifferential contribu-tions of AF-1 andAF-2 activities to the developmental functionsof RXR120572rdquo Development vol 128 no 11 pp 2049ndash2062 2001

[60] D Li T Li F Wang H Tian and H H Samuels ldquoFunctionalevidence for retinoid X receptor (RXR) as a nonsilent partner

ISRN Hepatology 15

in the thyroid hormone receptorRXR heterodimerrdquoMolecularand Cellular Biology vol 22 no 16 pp 5782ndash5792 2002

[61] F M Sladek W Zhong E Lai and J E Darnell Jr ldquoLiver-enriched transcription factor HNF-4 is a novel member ofthe steroid hormone receptor superfamilyrdquo Genes and Develop-ment vol 4 no 12 pp 2353ndash2365 1990

[62] K Yamagata H Furuta N Oda et al ldquoMutations in thehepatocyte nuclear factor-4120572 gene inmaturity-onset diabetes ofthe young (MODY1)rdquo Nature vol 384 no 6608 pp 458ndash4601996

[63] M Stoffel and S ADuncan ldquoThematurity-onset diabetes of theyoung (MODY1) transcription factor HNF4120572 regulates expres-sion of genes required for glucose transport and metabolismrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 24 pp 13209ndash13214 1997

[64] M Lehto P-O Bitzen B Isomaa et al ldquoMutation in the HNF-4120572 gene affects insulin secretion and triglyceride metabolismrdquoDiabetes vol 48 no 2 pp 423ndash425 1999

[65] G P Hayhurst Y-H Lee G Lambert J M Ward and F JGonzalez ldquoHepatocyte nuclear factor 4120572 (Nuclear receptor 2A1)is essential formaintenance of hepatic gene expression and lipidhomeostasisrdquo Molecular and Cellular Biology vol 21 no 4 pp1393ndash1403 2001

[66] U Roth K Jungermann and T Kietzmann ldquoActivation ofglucokinase gene expression by hepatic nuclear factor 4120572 inprimary hepatocytesrdquo Biochemical Journal vol 365 no 1 pp223ndash228 2002

[67] S Mandard R Stienstra P Escher et al ldquoGlycogen synthase2 is a novel target gene of peroxisome proliferator-activatedreceptorsrdquo Cellular and Molecular Life Sciences vol 64 no 9pp 1145ndash1157 2007

[68] F Rajas A Gautier I Bady S Montano and G MithieuxldquoPolyunsaturated fatty acyl coenzyme a suppress the glucose-6-phosphatase promoter activity bymodulating the DNA bindingof hepatocyte nuclear factor 4120572rdquo Journal of Biological Chemistryvol 277 no 18 pp 15736ndash15744 2002

[69] B Viollet A Kahn and M Raymondjean ldquoProtein kinase A-dependent phosphorylation modulates DNA-binding activityof hepatocyte nuclear factor 4rdquoMolecular and Cellular Biologyvol 17 no 8 pp 4208ndash4219 1997

[70] L Palanker J M Tennessen G Lam and C S Thum-mel ldquoDrosophila HNF4 regulates lipid mobilization and 120573-oxidationrdquo Cell Metabolism vol 9 no 3 pp 228ndash239 2009

[71] A Miura K Yamagata M Kakei et al ldquoHepatocyte nuclearfactor-4120572 is essential for glucose-stimulated insulin secretion bypancreatic 120573-cellsrdquo Journal of Biological Chemistry vol 281 no8 pp 5246ndash5257 2006

[72] R Bartoov-Shifman R Hertz H Wang C B Wollheim JBar-Tana and M D Walker ldquoActivation of the insulin genepromoter through a direct effect of hepatocyte nuclear factor4120572rdquo Journal of Biological Chemistry vol 277 no 29 pp 25914ndash25919 2002

[73] H Wang P Maechler P A Antinozzi K A Hagenfeldt andC B Wollheim ldquoHepatocyte nuclear factor 4120572 regulates theexpression of pancreatic 120573-cell genes implicated in glucosemetabolism and nutrient-induced insulin secretionrdquo Journal ofBiological Chemistry vol 275 no 46 pp 35953ndash35959 2000

[74] K Reue T Leff and J L Breslow ldquoHuman apolipoproteinCIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factorsrdquo Journal ofBiological Chemistry vol 263 no 14 pp 6857ndash6864 1988

[75] T Leff K Reue A Melian H Culver and J L BreslowldquoA regulatory element in the apoCIII promoter that directshepatic specific transcription binds to proteins in expressingand nonexpressing cell typesrdquo Journal of Biological Chemistryvol 264 no 27 pp 16132ndash16137 1989

[76] S N Lavrentiadou M Hadzopoulou-Cladaras D Kardassisand V I Zannis ldquoBinding specificity and modulation of thehuman apocIII promoter activity by heterodimers of ligand-dependent nuclear receptorsrdquo Biochemistry vol 38 no 3 pp964ndash975 1999

[77] T R Magee Y Cai M E El-Houseini J Locker and Y-JY Wan ldquoRetinoic acid mediates down-regulation of the 120572-fetoprotein gene through decreased expression of hepatocytenuclear factorsrdquo Journal of Biological Chemistry vol 273 no 45pp 30024ndash30032 1998

[78] A Qian Y Cai T R Magee and Y J Y Wan ldquoIdentificationof retinoic acid-responsive elements on the HNF1alpha andHNF4alpha genesrdquo Biochemical and Biophysical Research Com-munications vol 276 no 3 pp 837ndash842 2000

[79] H Nakshatri and P Chambon ldquoThe directly repeatedRG(GT)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites forRAR RXR HNF-4 and ARP-1 homo- and heterodimersrdquoJournal of Biological Chemistry vol 269 no 2 pp 890ndash9021994

[80] T Makita G Hernandez-Hoyos T H-P Chen H Wu E VRothenberg and H M Sucov ldquoA developmental transition indefinitive erythropoiesis erythropoietin expression is sequen-tially regulated by retinoic acid receptors andHNF4rdquoGenes andDevelopment vol 15 no 7 pp 889ndash901 2001

[81] T I Kambe J Tada-Kambe Y Kuge Y Yamaguchi-Iwai MNagao and R Sasaki ldquoRetinoic acid stimulates erythropoietingene transcription in embryonal carcinoma cells through thedirect repeat of a steroidthyroid hormone receptor responseelement half-site in the hypoxia-response enhancerrdquo Blood vol96 no 9 pp 3265ndash3271 2000

[82] F-J Lin J Qin K Tang S Y Tsai and M-J Tsai ldquoCoup drsquoEtatan orphan takes controlrdquo Endocrine Reviews vol 32 no 3 pp404ndash421 2011

[83] L-H Wang S Y Tsai R G Cook W G Beattie M-J Tsaiand BW OrsquoMalley ldquoCOUP transcription factor is a member ofthe steroid receptor superfamilyrdquoNature vol 340 no 6229 pp163ndash166 1989

[84] X Leng A J Cooney S Y Tsai and M-J Tsai ldquoMolecularmechanisms of COUP-TF-mediated transcriptional repressionevidence for transrepression and active repressionrdquo Molecularand Cellular Biology vol 16 no 5 pp 2332ndash2340 1996

[85] L Li X Xie J Qin et al ldquoThe nuclear orphan receptorCOUP-TFII plays an essential role in adipogenesis glucosehomeostasis and energy metabolismrdquo Cell Metabolism vol 9no 1 pp 77ndash87 2009

[86] F A Pereira Q Yuhong G Zhou M-J Tsai and S YTsai ldquoThe orphan nuclear receptor COUP-TFII is required forangiogenesis and heart developmentrdquo Genes and Developmentvol 13 no 8 pp 1037ndash1049 1999

[87] N Takamoto I Kurihara K Lee F J DeMayo M-J Tsai andS Y Tsai ldquoHaploinsufficiency of chicken ovalbumin upstreampromoter transcription factor II in female reproductionrdquoMolec-ular Endocrinology vol 19 no 9 pp 2299ndash2308 2005

[88] P Zhang M Bennoun C Gogard et al ldquoExpression of COUP-TFII in metabolic tissues during developmentrdquo Mechanisms ofDevelopment vol 119 no 1 pp 109ndash114 2002

16 ISRN Hepatology

[89] Z Xu S Yu C-H Hsu J Eguchi and E D Rosen ldquoTheorphan nuclear receptor chicken ovalbumin upstream pro-moter-transcription factor II is a critical regulator of adipogene-sisrdquoProceedings of theNationalAcademy of Sciences of theUnitedStates of America vol 105 no 7 pp 2421ndash2426 2008

[90] P Bardoux P Zhang D Flamez et al ldquoEssential role of chickenovalbumin upstreampromoter-transcription factor II in insulinsecretion and insulin sensitivity revealed by conditional geneknockoutrdquo Diabetes vol 54 no 5 pp 1357ndash1363 2005

[91] G Achatz B Holzl R Speckmayer C Hauser F Sandhoferand B Paulweber ldquoFunctional domains of the human orphanreceptor ARP-1COUP-TFII involved in active repression andtransrepressionrdquo Molecular and Cellular Biology vol 17 no 9pp 4914ndash4932 1997

[92] S A Kliewer K Umesono R A Heyman D J MangelsdorfJ A Dyck and R M Evans ldquoRetinoid X receptor-COUP-TFinteractionsmodulate retinoic acid signalingrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol89 no 4 pp 1448ndash1452 1992

[93] A J Cooney S Y Tsai BW OrsquoMalley andM-J Tsai ldquoChickenovalbumin upstreampromoter transcription factor (COUP-TF)dimers bind to different GGTCA response elements allowingCOUP-TF to repress hormonal induction of the vitamin D3thyroid hormone and retinoic acid receptorsrdquo Molecular andCellular Biology vol 12 no 9 pp 4153ndash4163 1992

[94] SW Kruse K Suino-Powell X E Zhou et al ldquoIdentification ofCOUP-TFII orphannuclear receptor as a retinoic acid-activatedreceptorrdquo PLoS Biology vol 6 no 9 Article ID e227 2008

[95] J P Berger T E Akiyama and P T Meinke ldquoPPARs thera-peutic targets for metabolic diseaserdquo Trends in PharmacologicalSciences vol 26 no 5 pp 244ndash251 2005

[96] JM Peters andF J Gonzalez ldquoSorting out the functional role(s)of peroxisome proliferator-activated receptor-120573120575 (PPAR120573120575)in cell proliferation and cancerrdquo Biochimica et Biophysica Actavol 1796 no 2 pp 230ndash241 2009

[97] A Tenenbaum and E Fisman ldquoBalanced pan-PPAR activatorbezafibrate in combination with statin comprehensive lipidscontrol and diabetes preventionrdquo Cardiovascular Diabetologyvol 11 no 1 article 140 2012

[98] O Braissant F Foufelle C Scotto M Dauca and W WahlildquoDifferential expression of peroxisome proliferator-activatedreceptors (PPARs) tissue distribution of PPAR-120572 -120573 and -120574 inthe adult ratrdquo Endocrinology vol 137 no 1 pp 354ndash366 1996

[99] H Higashiyama A N Billin Y Okamoto M Kinoshita andS Asano ldquoExpression profiling of Peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues usingtissue microarrayrdquo Histochemistry and Cell Biology vol 127 no5 pp 485ndash494 2007

[100] P S Jones R Savory P Barratt et al ldquoChromosomal local-isation inducibility tissue-specific expression and strain dif-ferences in three murine peroxisome-proliferator-activated-receptor genesrdquo European Journal of Biochemistry vol 233 no1 pp 219ndash226 1995

[101] S A Kliewer B M Forman B Blumberg et al ldquoDifferentialexpression and activation of a family of murine peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no15 pp 7355ndash7359 1994

[102] E E Girroir H E Hollingshead P He B Zhu G H Perdewand J M Peters ldquoQuantitative expression patterns of peroxi-some proliferator-activated receptor-120573120575 (PPAR120573120575) protein in

micerdquo Biochemical and Biophysical Research Communicationsvol 371 no 3 pp 456ndash461 2008

[103] P Escher O Braissant S Basu-Modak L Michalik W Wahliand B Desvergne ldquoRat PPARs quantitative analysis in adult rattissues and regulation in fasting and refeedingrdquo Endocrinologyvol 142 no 10 pp 4195ndash4202 2001

[104] D Auboeuf J Rieusset L Fajas et al ldquoTissue distributionand quantification of the expression of mRNAs of peroxi-some proliferator-activated receptors and liver X receptor-120572 inhumans no alteration in adipose tissue of obese and NIDDMpatientsrdquo Diabetes vol 46 no 8 pp 1319ndash1327 1997

[105] N ShawM Elholm andN Noy ldquoRetinoic acid is a high affinityselective ligand for the peroxisome proliferator-activated recep-tor 120573120575rdquo Journal of Biological Chemistry vol 278 no 43 pp41589ndash41592 2003

[106] G Wolf ldquoRetinoic acid as cause of cell proliferation or cellgrowth inhibition depending on activation of one of twodifferent nuclear receptorsrdquoNutrition Reviews vol 66 no 1 pp55ndash59 2008

[107] T T Schug D C Berry N S Shaw S N Travis and N NoyldquoOpposing effects of retinoic acid on cell growth result fromalternate activation of two different nuclear receptorsrdquo Cell vol129 no 4 pp 723ndash733 2007

[108] D C Berry and N Noy ldquoAll-trans-retinoic acid repressesobesity and insulin resistance by activating both peroxisomeproliferation-activated receptor 120573120575 and retinoic acid receptorrdquoMolecular and Cellular Biology vol 29 no 12 pp 3286ndash32962009

[109] D C Berry D DeSantis H Soltanian C M Croniger andN Noy ldquoRetinoic acid upregulates preadipocyte genes to blockadipogenesis and suppress diet-induced obesityrdquo Diabetes vol61 no 5 pp 1112ndash1121 2012

[110] M G Borland C Khozoie P P Albrecht et al ldquoStableover-expression of PPAR120573120575 and PPAR120574 to examine receptorsignaling in human HaCaT keratinocytesrdquo Cellular Signallingvol 23 no 12 pp 2039ndash2050 2011

[111] S E OrsquoSullivan and D A Kendall ldquoCannabinoid activationof peroxisome proliferator-activated receptors potential formodulation of inflammatory diseaserdquo Immunobiology vol 215no 8 pp 611ndash616 2010

[112] Z C Yan D Y Liu L L Zhang et al ldquoExercise reduces adiposetissue via cannabinoid receptor type 1 which is regulated byperoxisome proliferator-activated receptor-120575rdquo Biochemical andBiophysical Research Communications vol 354 no 2 pp 427ndash433 2007

[113] J D McGarry ldquoWhat if Minkowski had been ageusic Analternative angle on diabetesrdquo Science vol 258 no 5083 pp766ndash770 1992

[114] TMoore ldquoVitaminA and carotene the vitaminA reserve of theadult human being in health and diseaserdquo Biochemical Journalvol 31 no 1 pp 155ndash164 1937

[115] GWolfMD Lane and B C Johnson ldquoStudies on the functionof vitamin A in metabolismrdquo Journal of Biological Chemistryvol 225 no 2 pp 995ndash1008 1957

[116] Y Zhang R Li Y Li W Chen S Zhao and G Chen ldquoVitaminA status affects obesity development and hepatic expression ofkey genes for fuel metabolism in Zucker fatty ratsrdquoBiochemistryand Cell Biology vol 90 no 4 pp 548ndash557 2012

[117] M Singh V N Singh and T A Venkitasubramanian ldquoEarlyeffects of feeding excess vitamin A hepatic glycogen bloodlactic acid plasma nefa and glucose tolerance in ratsrdquo LifeSciences vol 7 no 5 pp 239ndash247 1968

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Hepatology 13

second question is whether RA synthesis in hepatocytesis a regulated process in response to dietary or hormonalstimulations If Raldh1 is a downstream gene of SREBP-1cit should be regulated when the SREBP-1c level changes Asthe expression of Srebp-1c responds to insulin stimulation andoxysterols the regulation of Raldh1 expression in the livershould be studied The third question is why it is RALDH1but not other RALDHs Specific inhibitors of RALDHsmay be needed to answer this question Last question iswhether we can attenuate insulin resistance by suppressingthe RALDH1 activity in the liver It has been shown thatRaldh1minusminus mice are still insulin sensitive when they are onan HFD [26] This has been attributed to the effects on theadipogenesis However the liver of those knockout mice hasreduced lipid synthesis [231] Further studies are warrantedto answer all of these questions Hopefully it can become anintervention point for the treatment of insulin resistance andmetabolic diseases

Acknowledgments

This work was financially supported by a research grantfrom Allen Foundation Inc (to Guoxun Chen) a start-up fund from the University of Tennessee at Knoxville (toGuoxun Chen) and a Scientist Development Grant fromthe AmericanHeart Association (09SDG2140003 to GuoxunChen) The author thanks his colleague Dr Lauren Gellar forreading through this paper and offering her edits

References

[1] F G Hopkins ldquoFeeding experiments illustrating the impor-tance of accessory factors in normal dietariesrdquo The Journal ofPhysiology vol 44 no 5-6 pp 425ndash460 1912

[2] K J Carpenter ldquoA short history of nutritional science part 3(1912ndash1944)rdquo Journal of Nutrition vol 133 no 10 pp 3023ndash30322003

[3] E V McCollum and M Davis ldquoThe necessity of certain lipinsin the diet during growthrdquo Journal of Biological Chemistry vol15 no 1 pp 167ndash175 1913

[4] T B Osborne and L B Mendel ldquoFeeding experiments with fat-free food mixturesrdquo Journal of Biological Chemistry vol 12 no1 pp 81ndash89 1912

[5] R D Semba ldquoOn the lsquoDiscoveryrsquo of Vitamin Ardquo Annals ofNutrition and Metabolism vol 61 no 3 pp 192ndash198 2012

[6] R Blomhoff and H K Blomhoff ldquoOverview of retinoidmetabolism and functionrdquo Journal of Neurobiology vol 66 no7 pp 606ndash630 2006

[7] A Sommer ldquoVitamin A deficiency and clinical disease anhistorical overviewrdquo Journal of Nutrition vol 138 no 10 pp1835ndash1839 2008

[8] K J Rothman L L Moore M R Singer U-S Nguyen SMannino and A Milunsky ldquoTeratogenicity of high vitamin Aintakerdquo The New England Journal of Medicine vol 333 no 21pp 1369ndash1373 1995

[9] S Bershad A Rubinstein and J R Paterniti Jr ldquoChanges inplasma lipids and lipoproteins during isotretinoin therapy foracnerdquoThe New England Journal of Medicine vol 313 no 16 pp981ndash985 1985

[10] N Rodondi R Darioli A-A Ramelet et al ldquoHigh risk forhyperlipidemia and the metabolic syndrome after an episodeof hypertriglyceridemia during 13-cis retinoic acid therapy foracne a pharmacogenetic studyrdquo Annals of Internal Medicinevol 136 no 8 pp 582ndash589 2002

[11] H-U Klor A Weizel M Augustin et al ldquoThe impact oforal vitamin A derivatives on lipid metabolism what recom-mendations can be derived for dealing with this issue in thedaily dermatological practicerdquo Journal of the German Societyof Dermatology vol 9 no 8 pp 600ndash607 2011

[12] R M Russell ldquoThe vitamin A spectrum from deficiency totoxicityrdquoThe American Journal of Clinical Nutrition vol 71 no4 pp 878ndash884 2000

[13] A C Ross B Caballero R J Cousins K L Tucker and T RZiegler Modern Nutrition in Health and Diseases 11th edition2012

[14] E H Harrison ldquoMechanisms of digestion and absorption ofdietary vitamin Ardquo Annual Review of Nutrition vol 25 no 1pp 87ndash103 2005

[15] M R Lakshman ldquoAlpha and omega of carotenoid cleavagerdquoJournal of Nutrition vol 134 no 1 pp 241ndash245 2004

[16] I Potrykus ldquoNutritionally enhanced rice to combat malnutri-tion disorders of the poorrdquo Nutrition Reviews vol 61 no 6 ppS101ndashS104 2003

[17] A Wyss ldquoCarotene oxygenases a new family of double bondcleavage enzymesrdquo Journal of Nutrition vol 134 no 1 pp 246ndash250 2004

[18] R Kawaguchi J Yu J Honda et al ldquoA membrane receptor forretinol binding protein mediates cellular uptake of vitamin ArdquoScience vol 315 no 5813 pp 820ndash825 2007

[19] P Alapatt F Guo S M Komanetsky et al ldquoLiver retinoltransporter and receptor for serum retinol-binding protein(RBP4)rdquo Journal of Biological Chemistry vol 288 no 2 pp1250ndash1265 2013

[20] A R Moise N Noy K Palczewski and W S Blaner ldquoDeliveryof retinoid-based therapies to target tissuesrdquo Biochemistry vol46 no 15 pp 4449ndash4458 2007

[21] G Duester ldquoFamilies of retinoid dehydrogenases regulatingvitamin A function Production of visual pigment and retinoicacidrdquo European Journal of Biochemistry vol 267 no 14 pp4315ndash4324 2000

[22] M Theodosiou V Laudet and M Schubert ldquoFrom carrotto clinic an overview of the retinoic acid signaling pathwayrdquoCellular andMolecular Life Sciences vol 67 no 9 pp 1423ndash14452010

[23] J L Napoli ldquoInteractions of retinoid binding proteins andenzymes in retinoidmetabolismrdquoBiochimica et BiophysicaActavol 1440 no 2-3 pp 139ndash162 1999

[24] X Chai M H E M Boerman Y Zhai and J L NapolildquoCloning of a cDNA for liver microsomal retinol dehydro-genase A tissue-specific short-chain alcohol dehydrogenaserdquoJournal of Biological Chemistry vol 270 no 8 pp 3900ndash39041995

[25] B X Wu G Moiseyev Y Chen B Rohrer R K Crouch andJ-XMa ldquoIdentification of RDH10 an all-trans retinol dehydro-genase in retinal Muller cellsrdquo Investigative Ophthalmology andVisual Science vol 45 no 11 pp 3857ndash3862 2004

[26] O Ziouzenkova G Orasanu M Sharlach et al ldquoRetinalde-hyde represses adipogenesis and diet-induced obesityrdquo NatureMedicine vol 13 no 6 pp 695ndash702 2007

14 ISRN Hepatology

[27] J L Napoli ldquoPhysiological insights into all-trans-retinoic acidbiosynthesisrdquo Biochimica et Biophysica Acta vol 1821 no 1 pp152ndash167 2012

[28] G Wolf ldquoTissue-specific increases in endogenous all-transretinoic acid possible contributing factor in ethanol toxicityrdquoNutrition Reviews vol 68 no 11 pp 689ndash692 2010

[29] P V Bhat J Labrecque JM Boutin A Lacroix andA YoshidaldquoCloning of a cDNA encoding rat aldehyde dehydrogenase withhigh activity for retinal oxidationrdquoGene vol 166 no 2 pp 303ndash306 1995

[30] M Lin M Zhang M Abraham S M Smith and J LNapoli ldquoMouse retinal dehydrogenase 4 (RALDH4) molecularcloning cellular expression and activity in 9-cis-retinoic acidbiosynthesis in intact cellsrdquo Journal of Biological Chemistry vol278 no 11 pp 9856ndash9861 2003

[31] F A Mic A Molotkov X Fan A E Cuenca and GDuester ldquoRALDH3 a retinaldehyde dehydrogenase that gener-ates retinoic acid is expressed in the ventral retina otic vesicleand olfactory pit during mouse developmentrdquo Mechanisms ofDevelopment vol 97 no 1-2 pp 227ndash230 2000

[32] X Wang P Penzes and J L Napoli ldquoCloning of a cDNAencoding an aldehyde dehydrogenase and its expression inEscherichia coli recognition of retinal as substraterdquo Journal ofBiological Chemistry vol 271 no 27 pp 16288ndash16293 1996

[33] A Molotkov and G Duester ldquoGenetic evidence that retinalde-hyde dehydrogenase Raldh1 (Aldh1a1) functions downstreamof alcohol dehydrogenase Adh1 in metabolism of retinol toretinoic acidrdquo Journal of Biological Chemistry vol 278 no 38pp 36085ndash36090 2003

[34] G Elizondo J Corchero E Sterneck and F J GonzalezldquoFeedback inhibition of the retinaldehyde dehydrogenase geneALDH1 by retinoic acid through retinoic acid receptor 120572and CCAATenhancer-binding protein 120573rdquo Journal of BiologicalChemistry vol 275 no 50 pp 39747ndash39753 2000

[35] G Elizondo I M Medina-Dıaz R Cruz F J Gonzalez and LVega ldquoRetinoic acid modulates retinaldehyde dehydrogenase 1gene expression through the induction of GADD153-CEBP120573interactionrdquo Biochemical Pharmacology vol 77 no 2 pp 248ndash257 2009

[36] K Fujiwara M Kikuchi K Horiguchi et al ldquoEstrogen receptoralpha regulates retinaldehyde dehydrogenase 1 expression in ratanterior pituitary cellsrdquo Endocrine Journal vol 56 no 8 pp963ndash973 2009

[37] K Fujiwara F Maekawa M Kikuchi S Takigami T Yadaand T Yashiro ldquoExpression of retinaldehyde dehydrogenase(RALDH)2 and RALDH3 but not RALDH1 in the developinganterior pituitary glands of ratsrdquo Cell and Tissue Research vol328 no 1 pp 129ndash135 2007

[38] GWolf ldquoThe enzymatic cleavage of 120573-carotene still controver-sialrdquo Nutrition Reviews vol 53 no 5 pp 134ndash137 1995

[39] S Abu-Abed P Dolle D Metzger B Beckett P Chambonand M Petkovich ldquoThe retinoic acid-metabolizing enzymeCYP26A1 is essential for normal hindbrain patterning verte-bral identity and development of posterior structuresrdquo Genesand Development vol 15 no 2 pp 226ndash240 2001

[40] M A Leo S Iida and C S Lieber ldquoRetinoic acid metabolismby a system reconstituted with cytochrome P-450rdquo Archives ofBiochemistry and Biophysics vol 234 no 1 pp 305ndash312 1984

[41] MA Leo JM Lasker J L Raucy C-I KimM Black andC SLieber ldquoMetabolism of retinol and retinoic acid by human livercytochrome P450IIC8rdquoArchives of Biochemistry and Biophysicsvol 269 no 1 pp 305ndash312 1989

[42] R Quere A Baudet B Cassinat et al ldquoPharmacogenomicanalysis of acute promyelocytic leukemia cells highlightsCYP26cytochrome metabolism in differential all-trans retinoic acidsensitivityrdquo Blood vol 109 no 10 pp 4450ndash4460 2007

[43] J AWhite B Beckett-Jones Y-D Guo et al ldquocDNA cloning ofhuman retinoic acid-metabolizing enzyme (hP450RAI) identi-fies a novel family of cytochromes p450 (CYP26)rdquo Journal ofBiological Chemistry vol 272 no 30 pp 18538ndash18541 1997

[44] Y Zhang R Zolfaghari Reza and A C Ross ldquoMultiple retinoicacid response elements cooperate to enhance the inducibility ofCYP26A1 gene expression in liverrdquo Gene vol 464 no 1-2 pp32ndash43 2010

[45] Y Li Y Zhang R Li et al ldquoThe hepatic raldh1 expression iselevated in Zucker fatty rats and its over-expression introducedthe retinal-induced Srebp-1c expression in INS-1 cellsrdquo PLoSONE vol 7 no 9 Article ID e45210 2012

[46] R M Evans ldquoThe nuclear receptor superfamily a Rosetta stonefor physiologyrdquo Molecular Endocrinology vol 19 no 6 pp1429ndash1438 2005

[47] P Chambon ldquoA decade of molecular biology of retinoic acidreceptorsrdquo FASEB Journal vol 10 no 9 pp 940ndash954 1996

[48] D J Mangelsdorf and RM Evans ldquoThe RXR heterodimers andorphan receptorsrdquo Cell vol 83 no 6 pp 841ndash850 1995

[49] J E Balmer and R Blomhoff ldquoA robust characterization ofretinoic acid response elements based on a comparison of sitesin three speciesrdquo Journal of Steroid Biochemistry and MolecularBiology vol 96 no 5 pp 347ndash354 2005

[50] R Kurokawa J DiRenzo M Boehm et al ldquoRegulation ofretinoid signalling by receptor polarity and allosteric control ofligand bindingrdquo Nature vol 371 no 6497 pp 528ndash531 1994

[51] A Cvekl and W-L Wang ldquoRetinoic acid signaling in mam-malian eye developmentrdquo Experimental Eye Research vol 89no 3 pp 280ndash291 2009

[52] V Dupe M Davenne J Brocard et al ldquoIn vivo functional anal-ysis of the Hoxa-1 31015840 retinoic acid response element (31015840RARE)rdquoDevelopment vol 124 no 2 pp 399ndash410 1997

[53] A C Ross ldquoRetinoid production and catabolism role of dietin regulating retinol esterification and retinoic acid oxidationrdquoJournal of Nutrition vol 133 no 1 pp 291ndash296 2003

[54] T Moore and P D Holmes ldquoThe production of experimentalvitamin A deficiency in rats andmicerdquo Laboratory Animals vol5 no 2 pp 239ndash250 1971

[55] A C Ross and E H Harrison ldquoVitamin A and carotenoidsrdquoin Handbook of Vitamins D E McCormick R R Rucker J WSuttie et al Eds CRC Press Boca Raton Fla USA 4th edition2006

[56] A Chawta J J Repa R M Evans and D J MangelsdorfldquoNuclear receptors and lipid physiology opening the x-filesrdquoScience vol 294 no 5548 pp 1866ndash1870 2001

[57] C K Glass and M G Rosenfeld ldquoThe coregulator exchangein transcriptional functions of nuclear receptorsrdquo Genes andDevelopment vol 14 no 2 pp 121ndash141 2000

[58] A L Bookout Y Jeong M Downes R T Yu R M EvansandD JMangelsdorf ldquoAnatomical profiling of nuclear receptorexpression reveals a hierarchical transcriptional networkrdquo Cellvol 126 no 4 pp 789ndash799 2006

[59] B Mascrez M Mark W Krezel et al ldquoDifferential contribu-tions of AF-1 andAF-2 activities to the developmental functionsof RXR120572rdquo Development vol 128 no 11 pp 2049ndash2062 2001

[60] D Li T Li F Wang H Tian and H H Samuels ldquoFunctionalevidence for retinoid X receptor (RXR) as a nonsilent partner

ISRN Hepatology 15

in the thyroid hormone receptorRXR heterodimerrdquoMolecularand Cellular Biology vol 22 no 16 pp 5782ndash5792 2002

[61] F M Sladek W Zhong E Lai and J E Darnell Jr ldquoLiver-enriched transcription factor HNF-4 is a novel member ofthe steroid hormone receptor superfamilyrdquo Genes and Develop-ment vol 4 no 12 pp 2353ndash2365 1990

[62] K Yamagata H Furuta N Oda et al ldquoMutations in thehepatocyte nuclear factor-4120572 gene inmaturity-onset diabetes ofthe young (MODY1)rdquo Nature vol 384 no 6608 pp 458ndash4601996

[63] M Stoffel and S ADuncan ldquoThematurity-onset diabetes of theyoung (MODY1) transcription factor HNF4120572 regulates expres-sion of genes required for glucose transport and metabolismrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 24 pp 13209ndash13214 1997

[64] M Lehto P-O Bitzen B Isomaa et al ldquoMutation in the HNF-4120572 gene affects insulin secretion and triglyceride metabolismrdquoDiabetes vol 48 no 2 pp 423ndash425 1999

[65] G P Hayhurst Y-H Lee G Lambert J M Ward and F JGonzalez ldquoHepatocyte nuclear factor 4120572 (Nuclear receptor 2A1)is essential formaintenance of hepatic gene expression and lipidhomeostasisrdquo Molecular and Cellular Biology vol 21 no 4 pp1393ndash1403 2001

[66] U Roth K Jungermann and T Kietzmann ldquoActivation ofglucokinase gene expression by hepatic nuclear factor 4120572 inprimary hepatocytesrdquo Biochemical Journal vol 365 no 1 pp223ndash228 2002

[67] S Mandard R Stienstra P Escher et al ldquoGlycogen synthase2 is a novel target gene of peroxisome proliferator-activatedreceptorsrdquo Cellular and Molecular Life Sciences vol 64 no 9pp 1145ndash1157 2007

[68] F Rajas A Gautier I Bady S Montano and G MithieuxldquoPolyunsaturated fatty acyl coenzyme a suppress the glucose-6-phosphatase promoter activity bymodulating the DNA bindingof hepatocyte nuclear factor 4120572rdquo Journal of Biological Chemistryvol 277 no 18 pp 15736ndash15744 2002

[69] B Viollet A Kahn and M Raymondjean ldquoProtein kinase A-dependent phosphorylation modulates DNA-binding activityof hepatocyte nuclear factor 4rdquoMolecular and Cellular Biologyvol 17 no 8 pp 4208ndash4219 1997

[70] L Palanker J M Tennessen G Lam and C S Thum-mel ldquoDrosophila HNF4 regulates lipid mobilization and 120573-oxidationrdquo Cell Metabolism vol 9 no 3 pp 228ndash239 2009

[71] A Miura K Yamagata M Kakei et al ldquoHepatocyte nuclearfactor-4120572 is essential for glucose-stimulated insulin secretion bypancreatic 120573-cellsrdquo Journal of Biological Chemistry vol 281 no8 pp 5246ndash5257 2006

[72] R Bartoov-Shifman R Hertz H Wang C B Wollheim JBar-Tana and M D Walker ldquoActivation of the insulin genepromoter through a direct effect of hepatocyte nuclear factor4120572rdquo Journal of Biological Chemistry vol 277 no 29 pp 25914ndash25919 2002

[73] H Wang P Maechler P A Antinozzi K A Hagenfeldt andC B Wollheim ldquoHepatocyte nuclear factor 4120572 regulates theexpression of pancreatic 120573-cell genes implicated in glucosemetabolism and nutrient-induced insulin secretionrdquo Journal ofBiological Chemistry vol 275 no 46 pp 35953ndash35959 2000

[74] K Reue T Leff and J L Breslow ldquoHuman apolipoproteinCIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factorsrdquo Journal ofBiological Chemistry vol 263 no 14 pp 6857ndash6864 1988

[75] T Leff K Reue A Melian H Culver and J L BreslowldquoA regulatory element in the apoCIII promoter that directshepatic specific transcription binds to proteins in expressingand nonexpressing cell typesrdquo Journal of Biological Chemistryvol 264 no 27 pp 16132ndash16137 1989

[76] S N Lavrentiadou M Hadzopoulou-Cladaras D Kardassisand V I Zannis ldquoBinding specificity and modulation of thehuman apocIII promoter activity by heterodimers of ligand-dependent nuclear receptorsrdquo Biochemistry vol 38 no 3 pp964ndash975 1999

[77] T R Magee Y Cai M E El-Houseini J Locker and Y-JY Wan ldquoRetinoic acid mediates down-regulation of the 120572-fetoprotein gene through decreased expression of hepatocytenuclear factorsrdquo Journal of Biological Chemistry vol 273 no 45pp 30024ndash30032 1998

[78] A Qian Y Cai T R Magee and Y J Y Wan ldquoIdentificationof retinoic acid-responsive elements on the HNF1alpha andHNF4alpha genesrdquo Biochemical and Biophysical Research Com-munications vol 276 no 3 pp 837ndash842 2000

[79] H Nakshatri and P Chambon ldquoThe directly repeatedRG(GT)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites forRAR RXR HNF-4 and ARP-1 homo- and heterodimersrdquoJournal of Biological Chemistry vol 269 no 2 pp 890ndash9021994

[80] T Makita G Hernandez-Hoyos T H-P Chen H Wu E VRothenberg and H M Sucov ldquoA developmental transition indefinitive erythropoiesis erythropoietin expression is sequen-tially regulated by retinoic acid receptors andHNF4rdquoGenes andDevelopment vol 15 no 7 pp 889ndash901 2001

[81] T I Kambe J Tada-Kambe Y Kuge Y Yamaguchi-Iwai MNagao and R Sasaki ldquoRetinoic acid stimulates erythropoietingene transcription in embryonal carcinoma cells through thedirect repeat of a steroidthyroid hormone receptor responseelement half-site in the hypoxia-response enhancerrdquo Blood vol96 no 9 pp 3265ndash3271 2000

[82] F-J Lin J Qin K Tang S Y Tsai and M-J Tsai ldquoCoup drsquoEtatan orphan takes controlrdquo Endocrine Reviews vol 32 no 3 pp404ndash421 2011

[83] L-H Wang S Y Tsai R G Cook W G Beattie M-J Tsaiand BW OrsquoMalley ldquoCOUP transcription factor is a member ofthe steroid receptor superfamilyrdquoNature vol 340 no 6229 pp163ndash166 1989

[84] X Leng A J Cooney S Y Tsai and M-J Tsai ldquoMolecularmechanisms of COUP-TF-mediated transcriptional repressionevidence for transrepression and active repressionrdquo Molecularand Cellular Biology vol 16 no 5 pp 2332ndash2340 1996

[85] L Li X Xie J Qin et al ldquoThe nuclear orphan receptorCOUP-TFII plays an essential role in adipogenesis glucosehomeostasis and energy metabolismrdquo Cell Metabolism vol 9no 1 pp 77ndash87 2009

[86] F A Pereira Q Yuhong G Zhou M-J Tsai and S YTsai ldquoThe orphan nuclear receptor COUP-TFII is required forangiogenesis and heart developmentrdquo Genes and Developmentvol 13 no 8 pp 1037ndash1049 1999

[87] N Takamoto I Kurihara K Lee F J DeMayo M-J Tsai andS Y Tsai ldquoHaploinsufficiency of chicken ovalbumin upstreampromoter transcription factor II in female reproductionrdquoMolec-ular Endocrinology vol 19 no 9 pp 2299ndash2308 2005

[88] P Zhang M Bennoun C Gogard et al ldquoExpression of COUP-TFII in metabolic tissues during developmentrdquo Mechanisms ofDevelopment vol 119 no 1 pp 109ndash114 2002

16 ISRN Hepatology

[89] Z Xu S Yu C-H Hsu J Eguchi and E D Rosen ldquoTheorphan nuclear receptor chicken ovalbumin upstream pro-moter-transcription factor II is a critical regulator of adipogene-sisrdquoProceedings of theNationalAcademy of Sciences of theUnitedStates of America vol 105 no 7 pp 2421ndash2426 2008

[90] P Bardoux P Zhang D Flamez et al ldquoEssential role of chickenovalbumin upstreampromoter-transcription factor II in insulinsecretion and insulin sensitivity revealed by conditional geneknockoutrdquo Diabetes vol 54 no 5 pp 1357ndash1363 2005

[91] G Achatz B Holzl R Speckmayer C Hauser F Sandhoferand B Paulweber ldquoFunctional domains of the human orphanreceptor ARP-1COUP-TFII involved in active repression andtransrepressionrdquo Molecular and Cellular Biology vol 17 no 9pp 4914ndash4932 1997

[92] S A Kliewer K Umesono R A Heyman D J MangelsdorfJ A Dyck and R M Evans ldquoRetinoid X receptor-COUP-TFinteractionsmodulate retinoic acid signalingrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol89 no 4 pp 1448ndash1452 1992

[93] A J Cooney S Y Tsai BW OrsquoMalley andM-J Tsai ldquoChickenovalbumin upstreampromoter transcription factor (COUP-TF)dimers bind to different GGTCA response elements allowingCOUP-TF to repress hormonal induction of the vitamin D3thyroid hormone and retinoic acid receptorsrdquo Molecular andCellular Biology vol 12 no 9 pp 4153ndash4163 1992

[94] SW Kruse K Suino-Powell X E Zhou et al ldquoIdentification ofCOUP-TFII orphannuclear receptor as a retinoic acid-activatedreceptorrdquo PLoS Biology vol 6 no 9 Article ID e227 2008

[95] J P Berger T E Akiyama and P T Meinke ldquoPPARs thera-peutic targets for metabolic diseaserdquo Trends in PharmacologicalSciences vol 26 no 5 pp 244ndash251 2005

[96] JM Peters andF J Gonzalez ldquoSorting out the functional role(s)of peroxisome proliferator-activated receptor-120573120575 (PPAR120573120575)in cell proliferation and cancerrdquo Biochimica et Biophysica Actavol 1796 no 2 pp 230ndash241 2009

[97] A Tenenbaum and E Fisman ldquoBalanced pan-PPAR activatorbezafibrate in combination with statin comprehensive lipidscontrol and diabetes preventionrdquo Cardiovascular Diabetologyvol 11 no 1 article 140 2012

[98] O Braissant F Foufelle C Scotto M Dauca and W WahlildquoDifferential expression of peroxisome proliferator-activatedreceptors (PPARs) tissue distribution of PPAR-120572 -120573 and -120574 inthe adult ratrdquo Endocrinology vol 137 no 1 pp 354ndash366 1996

[99] H Higashiyama A N Billin Y Okamoto M Kinoshita andS Asano ldquoExpression profiling of Peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues usingtissue microarrayrdquo Histochemistry and Cell Biology vol 127 no5 pp 485ndash494 2007

[100] P S Jones R Savory P Barratt et al ldquoChromosomal local-isation inducibility tissue-specific expression and strain dif-ferences in three murine peroxisome-proliferator-activated-receptor genesrdquo European Journal of Biochemistry vol 233 no1 pp 219ndash226 1995

[101] S A Kliewer B M Forman B Blumberg et al ldquoDifferentialexpression and activation of a family of murine peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no15 pp 7355ndash7359 1994

[102] E E Girroir H E Hollingshead P He B Zhu G H Perdewand J M Peters ldquoQuantitative expression patterns of peroxi-some proliferator-activated receptor-120573120575 (PPAR120573120575) protein in

micerdquo Biochemical and Biophysical Research Communicationsvol 371 no 3 pp 456ndash461 2008

[103] P Escher O Braissant S Basu-Modak L Michalik W Wahliand B Desvergne ldquoRat PPARs quantitative analysis in adult rattissues and regulation in fasting and refeedingrdquo Endocrinologyvol 142 no 10 pp 4195ndash4202 2001

[104] D Auboeuf J Rieusset L Fajas et al ldquoTissue distributionand quantification of the expression of mRNAs of peroxi-some proliferator-activated receptors and liver X receptor-120572 inhumans no alteration in adipose tissue of obese and NIDDMpatientsrdquo Diabetes vol 46 no 8 pp 1319ndash1327 1997

[105] N ShawM Elholm andN Noy ldquoRetinoic acid is a high affinityselective ligand for the peroxisome proliferator-activated recep-tor 120573120575rdquo Journal of Biological Chemistry vol 278 no 43 pp41589ndash41592 2003

[106] G Wolf ldquoRetinoic acid as cause of cell proliferation or cellgrowth inhibition depending on activation of one of twodifferent nuclear receptorsrdquoNutrition Reviews vol 66 no 1 pp55ndash59 2008

[107] T T Schug D C Berry N S Shaw S N Travis and N NoyldquoOpposing effects of retinoic acid on cell growth result fromalternate activation of two different nuclear receptorsrdquo Cell vol129 no 4 pp 723ndash733 2007

[108] D C Berry and N Noy ldquoAll-trans-retinoic acid repressesobesity and insulin resistance by activating both peroxisomeproliferation-activated receptor 120573120575 and retinoic acid receptorrdquoMolecular and Cellular Biology vol 29 no 12 pp 3286ndash32962009

[109] D C Berry D DeSantis H Soltanian C M Croniger andN Noy ldquoRetinoic acid upregulates preadipocyte genes to blockadipogenesis and suppress diet-induced obesityrdquo Diabetes vol61 no 5 pp 1112ndash1121 2012

[110] M G Borland C Khozoie P P Albrecht et al ldquoStableover-expression of PPAR120573120575 and PPAR120574 to examine receptorsignaling in human HaCaT keratinocytesrdquo Cellular Signallingvol 23 no 12 pp 2039ndash2050 2011

[111] S E OrsquoSullivan and D A Kendall ldquoCannabinoid activationof peroxisome proliferator-activated receptors potential formodulation of inflammatory diseaserdquo Immunobiology vol 215no 8 pp 611ndash616 2010

[112] Z C Yan D Y Liu L L Zhang et al ldquoExercise reduces adiposetissue via cannabinoid receptor type 1 which is regulated byperoxisome proliferator-activated receptor-120575rdquo Biochemical andBiophysical Research Communications vol 354 no 2 pp 427ndash433 2007

[113] J D McGarry ldquoWhat if Minkowski had been ageusic Analternative angle on diabetesrdquo Science vol 258 no 5083 pp766ndash770 1992

[114] TMoore ldquoVitaminA and carotene the vitaminA reserve of theadult human being in health and diseaserdquo Biochemical Journalvol 31 no 1 pp 155ndash164 1937

[115] GWolfMD Lane and B C Johnson ldquoStudies on the functionof vitamin A in metabolismrdquo Journal of Biological Chemistryvol 225 no 2 pp 995ndash1008 1957

[116] Y Zhang R Li Y Li W Chen S Zhao and G Chen ldquoVitaminA status affects obesity development and hepatic expression ofkey genes for fuel metabolism in Zucker fatty ratsrdquoBiochemistryand Cell Biology vol 90 no 4 pp 548ndash557 2012

[117] M Singh V N Singh and T A Venkitasubramanian ldquoEarlyeffects of feeding excess vitamin A hepatic glycogen bloodlactic acid plasma nefa and glucose tolerance in ratsrdquo LifeSciences vol 7 no 5 pp 239ndash247 1968

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

14 ISRN Hepatology

[27] J L Napoli ldquoPhysiological insights into all-trans-retinoic acidbiosynthesisrdquo Biochimica et Biophysica Acta vol 1821 no 1 pp152ndash167 2012

[28] G Wolf ldquoTissue-specific increases in endogenous all-transretinoic acid possible contributing factor in ethanol toxicityrdquoNutrition Reviews vol 68 no 11 pp 689ndash692 2010

[29] P V Bhat J Labrecque JM Boutin A Lacroix andA YoshidaldquoCloning of a cDNA encoding rat aldehyde dehydrogenase withhigh activity for retinal oxidationrdquoGene vol 166 no 2 pp 303ndash306 1995

[30] M Lin M Zhang M Abraham S M Smith and J LNapoli ldquoMouse retinal dehydrogenase 4 (RALDH4) molecularcloning cellular expression and activity in 9-cis-retinoic acidbiosynthesis in intact cellsrdquo Journal of Biological Chemistry vol278 no 11 pp 9856ndash9861 2003

[31] F A Mic A Molotkov X Fan A E Cuenca and GDuester ldquoRALDH3 a retinaldehyde dehydrogenase that gener-ates retinoic acid is expressed in the ventral retina otic vesicleand olfactory pit during mouse developmentrdquo Mechanisms ofDevelopment vol 97 no 1-2 pp 227ndash230 2000

[32] X Wang P Penzes and J L Napoli ldquoCloning of a cDNAencoding an aldehyde dehydrogenase and its expression inEscherichia coli recognition of retinal as substraterdquo Journal ofBiological Chemistry vol 271 no 27 pp 16288ndash16293 1996

[33] A Molotkov and G Duester ldquoGenetic evidence that retinalde-hyde dehydrogenase Raldh1 (Aldh1a1) functions downstreamof alcohol dehydrogenase Adh1 in metabolism of retinol toretinoic acidrdquo Journal of Biological Chemistry vol 278 no 38pp 36085ndash36090 2003

[34] G Elizondo J Corchero E Sterneck and F J GonzalezldquoFeedback inhibition of the retinaldehyde dehydrogenase geneALDH1 by retinoic acid through retinoic acid receptor 120572and CCAATenhancer-binding protein 120573rdquo Journal of BiologicalChemistry vol 275 no 50 pp 39747ndash39753 2000

[35] G Elizondo I M Medina-Dıaz R Cruz F J Gonzalez and LVega ldquoRetinoic acid modulates retinaldehyde dehydrogenase 1gene expression through the induction of GADD153-CEBP120573interactionrdquo Biochemical Pharmacology vol 77 no 2 pp 248ndash257 2009

[36] K Fujiwara M Kikuchi K Horiguchi et al ldquoEstrogen receptoralpha regulates retinaldehyde dehydrogenase 1 expression in ratanterior pituitary cellsrdquo Endocrine Journal vol 56 no 8 pp963ndash973 2009

[37] K Fujiwara F Maekawa M Kikuchi S Takigami T Yadaand T Yashiro ldquoExpression of retinaldehyde dehydrogenase(RALDH)2 and RALDH3 but not RALDH1 in the developinganterior pituitary glands of ratsrdquo Cell and Tissue Research vol328 no 1 pp 129ndash135 2007

[38] GWolf ldquoThe enzymatic cleavage of 120573-carotene still controver-sialrdquo Nutrition Reviews vol 53 no 5 pp 134ndash137 1995

[39] S Abu-Abed P Dolle D Metzger B Beckett P Chambonand M Petkovich ldquoThe retinoic acid-metabolizing enzymeCYP26A1 is essential for normal hindbrain patterning verte-bral identity and development of posterior structuresrdquo Genesand Development vol 15 no 2 pp 226ndash240 2001

[40] M A Leo S Iida and C S Lieber ldquoRetinoic acid metabolismby a system reconstituted with cytochrome P-450rdquo Archives ofBiochemistry and Biophysics vol 234 no 1 pp 305ndash312 1984

[41] MA Leo JM Lasker J L Raucy C-I KimM Black andC SLieber ldquoMetabolism of retinol and retinoic acid by human livercytochrome P450IIC8rdquoArchives of Biochemistry and Biophysicsvol 269 no 1 pp 305ndash312 1989

[42] R Quere A Baudet B Cassinat et al ldquoPharmacogenomicanalysis of acute promyelocytic leukemia cells highlightsCYP26cytochrome metabolism in differential all-trans retinoic acidsensitivityrdquo Blood vol 109 no 10 pp 4450ndash4460 2007

[43] J AWhite B Beckett-Jones Y-D Guo et al ldquocDNA cloning ofhuman retinoic acid-metabolizing enzyme (hP450RAI) identi-fies a novel family of cytochromes p450 (CYP26)rdquo Journal ofBiological Chemistry vol 272 no 30 pp 18538ndash18541 1997

[44] Y Zhang R Zolfaghari Reza and A C Ross ldquoMultiple retinoicacid response elements cooperate to enhance the inducibility ofCYP26A1 gene expression in liverrdquo Gene vol 464 no 1-2 pp32ndash43 2010

[45] Y Li Y Zhang R Li et al ldquoThe hepatic raldh1 expression iselevated in Zucker fatty rats and its over-expression introducedthe retinal-induced Srebp-1c expression in INS-1 cellsrdquo PLoSONE vol 7 no 9 Article ID e45210 2012

[46] R M Evans ldquoThe nuclear receptor superfamily a Rosetta stonefor physiologyrdquo Molecular Endocrinology vol 19 no 6 pp1429ndash1438 2005

[47] P Chambon ldquoA decade of molecular biology of retinoic acidreceptorsrdquo FASEB Journal vol 10 no 9 pp 940ndash954 1996

[48] D J Mangelsdorf and RM Evans ldquoThe RXR heterodimers andorphan receptorsrdquo Cell vol 83 no 6 pp 841ndash850 1995

[49] J E Balmer and R Blomhoff ldquoA robust characterization ofretinoic acid response elements based on a comparison of sitesin three speciesrdquo Journal of Steroid Biochemistry and MolecularBiology vol 96 no 5 pp 347ndash354 2005

[50] R Kurokawa J DiRenzo M Boehm et al ldquoRegulation ofretinoid signalling by receptor polarity and allosteric control ofligand bindingrdquo Nature vol 371 no 6497 pp 528ndash531 1994

[51] A Cvekl and W-L Wang ldquoRetinoic acid signaling in mam-malian eye developmentrdquo Experimental Eye Research vol 89no 3 pp 280ndash291 2009

[52] V Dupe M Davenne J Brocard et al ldquoIn vivo functional anal-ysis of the Hoxa-1 31015840 retinoic acid response element (31015840RARE)rdquoDevelopment vol 124 no 2 pp 399ndash410 1997

[53] A C Ross ldquoRetinoid production and catabolism role of dietin regulating retinol esterification and retinoic acid oxidationrdquoJournal of Nutrition vol 133 no 1 pp 291ndash296 2003

[54] T Moore and P D Holmes ldquoThe production of experimentalvitamin A deficiency in rats andmicerdquo Laboratory Animals vol5 no 2 pp 239ndash250 1971

[55] A C Ross and E H Harrison ldquoVitamin A and carotenoidsrdquoin Handbook of Vitamins D E McCormick R R Rucker J WSuttie et al Eds CRC Press Boca Raton Fla USA 4th edition2006

[56] A Chawta J J Repa R M Evans and D J MangelsdorfldquoNuclear receptors and lipid physiology opening the x-filesrdquoScience vol 294 no 5548 pp 1866ndash1870 2001

[57] C K Glass and M G Rosenfeld ldquoThe coregulator exchangein transcriptional functions of nuclear receptorsrdquo Genes andDevelopment vol 14 no 2 pp 121ndash141 2000

[58] A L Bookout Y Jeong M Downes R T Yu R M EvansandD JMangelsdorf ldquoAnatomical profiling of nuclear receptorexpression reveals a hierarchical transcriptional networkrdquo Cellvol 126 no 4 pp 789ndash799 2006

[59] B Mascrez M Mark W Krezel et al ldquoDifferential contribu-tions of AF-1 andAF-2 activities to the developmental functionsof RXR120572rdquo Development vol 128 no 11 pp 2049ndash2062 2001

[60] D Li T Li F Wang H Tian and H H Samuels ldquoFunctionalevidence for retinoid X receptor (RXR) as a nonsilent partner

ISRN Hepatology 15

in the thyroid hormone receptorRXR heterodimerrdquoMolecularand Cellular Biology vol 22 no 16 pp 5782ndash5792 2002

[61] F M Sladek W Zhong E Lai and J E Darnell Jr ldquoLiver-enriched transcription factor HNF-4 is a novel member ofthe steroid hormone receptor superfamilyrdquo Genes and Develop-ment vol 4 no 12 pp 2353ndash2365 1990

[62] K Yamagata H Furuta N Oda et al ldquoMutations in thehepatocyte nuclear factor-4120572 gene inmaturity-onset diabetes ofthe young (MODY1)rdquo Nature vol 384 no 6608 pp 458ndash4601996

[63] M Stoffel and S ADuncan ldquoThematurity-onset diabetes of theyoung (MODY1) transcription factor HNF4120572 regulates expres-sion of genes required for glucose transport and metabolismrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 24 pp 13209ndash13214 1997

[64] M Lehto P-O Bitzen B Isomaa et al ldquoMutation in the HNF-4120572 gene affects insulin secretion and triglyceride metabolismrdquoDiabetes vol 48 no 2 pp 423ndash425 1999

[65] G P Hayhurst Y-H Lee G Lambert J M Ward and F JGonzalez ldquoHepatocyte nuclear factor 4120572 (Nuclear receptor 2A1)is essential formaintenance of hepatic gene expression and lipidhomeostasisrdquo Molecular and Cellular Biology vol 21 no 4 pp1393ndash1403 2001

[66] U Roth K Jungermann and T Kietzmann ldquoActivation ofglucokinase gene expression by hepatic nuclear factor 4120572 inprimary hepatocytesrdquo Biochemical Journal vol 365 no 1 pp223ndash228 2002

[67] S Mandard R Stienstra P Escher et al ldquoGlycogen synthase2 is a novel target gene of peroxisome proliferator-activatedreceptorsrdquo Cellular and Molecular Life Sciences vol 64 no 9pp 1145ndash1157 2007

[68] F Rajas A Gautier I Bady S Montano and G MithieuxldquoPolyunsaturated fatty acyl coenzyme a suppress the glucose-6-phosphatase promoter activity bymodulating the DNA bindingof hepatocyte nuclear factor 4120572rdquo Journal of Biological Chemistryvol 277 no 18 pp 15736ndash15744 2002

[69] B Viollet A Kahn and M Raymondjean ldquoProtein kinase A-dependent phosphorylation modulates DNA-binding activityof hepatocyte nuclear factor 4rdquoMolecular and Cellular Biologyvol 17 no 8 pp 4208ndash4219 1997

[70] L Palanker J M Tennessen G Lam and C S Thum-mel ldquoDrosophila HNF4 regulates lipid mobilization and 120573-oxidationrdquo Cell Metabolism vol 9 no 3 pp 228ndash239 2009

[71] A Miura K Yamagata M Kakei et al ldquoHepatocyte nuclearfactor-4120572 is essential for glucose-stimulated insulin secretion bypancreatic 120573-cellsrdquo Journal of Biological Chemistry vol 281 no8 pp 5246ndash5257 2006

[72] R Bartoov-Shifman R Hertz H Wang C B Wollheim JBar-Tana and M D Walker ldquoActivation of the insulin genepromoter through a direct effect of hepatocyte nuclear factor4120572rdquo Journal of Biological Chemistry vol 277 no 29 pp 25914ndash25919 2002

[73] H Wang P Maechler P A Antinozzi K A Hagenfeldt andC B Wollheim ldquoHepatocyte nuclear factor 4120572 regulates theexpression of pancreatic 120573-cell genes implicated in glucosemetabolism and nutrient-induced insulin secretionrdquo Journal ofBiological Chemistry vol 275 no 46 pp 35953ndash35959 2000

[74] K Reue T Leff and J L Breslow ldquoHuman apolipoproteinCIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factorsrdquo Journal ofBiological Chemistry vol 263 no 14 pp 6857ndash6864 1988

[75] T Leff K Reue A Melian H Culver and J L BreslowldquoA regulatory element in the apoCIII promoter that directshepatic specific transcription binds to proteins in expressingand nonexpressing cell typesrdquo Journal of Biological Chemistryvol 264 no 27 pp 16132ndash16137 1989

[76] S N Lavrentiadou M Hadzopoulou-Cladaras D Kardassisand V I Zannis ldquoBinding specificity and modulation of thehuman apocIII promoter activity by heterodimers of ligand-dependent nuclear receptorsrdquo Biochemistry vol 38 no 3 pp964ndash975 1999

[77] T R Magee Y Cai M E El-Houseini J Locker and Y-JY Wan ldquoRetinoic acid mediates down-regulation of the 120572-fetoprotein gene through decreased expression of hepatocytenuclear factorsrdquo Journal of Biological Chemistry vol 273 no 45pp 30024ndash30032 1998

[78] A Qian Y Cai T R Magee and Y J Y Wan ldquoIdentificationof retinoic acid-responsive elements on the HNF1alpha andHNF4alpha genesrdquo Biochemical and Biophysical Research Com-munications vol 276 no 3 pp 837ndash842 2000

[79] H Nakshatri and P Chambon ldquoThe directly repeatedRG(GT)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites forRAR RXR HNF-4 and ARP-1 homo- and heterodimersrdquoJournal of Biological Chemistry vol 269 no 2 pp 890ndash9021994

[80] T Makita G Hernandez-Hoyos T H-P Chen H Wu E VRothenberg and H M Sucov ldquoA developmental transition indefinitive erythropoiesis erythropoietin expression is sequen-tially regulated by retinoic acid receptors andHNF4rdquoGenes andDevelopment vol 15 no 7 pp 889ndash901 2001

[81] T I Kambe J Tada-Kambe Y Kuge Y Yamaguchi-Iwai MNagao and R Sasaki ldquoRetinoic acid stimulates erythropoietingene transcription in embryonal carcinoma cells through thedirect repeat of a steroidthyroid hormone receptor responseelement half-site in the hypoxia-response enhancerrdquo Blood vol96 no 9 pp 3265ndash3271 2000

[82] F-J Lin J Qin K Tang S Y Tsai and M-J Tsai ldquoCoup drsquoEtatan orphan takes controlrdquo Endocrine Reviews vol 32 no 3 pp404ndash421 2011

[83] L-H Wang S Y Tsai R G Cook W G Beattie M-J Tsaiand BW OrsquoMalley ldquoCOUP transcription factor is a member ofthe steroid receptor superfamilyrdquoNature vol 340 no 6229 pp163ndash166 1989

[84] X Leng A J Cooney S Y Tsai and M-J Tsai ldquoMolecularmechanisms of COUP-TF-mediated transcriptional repressionevidence for transrepression and active repressionrdquo Molecularand Cellular Biology vol 16 no 5 pp 2332ndash2340 1996

[85] L Li X Xie J Qin et al ldquoThe nuclear orphan receptorCOUP-TFII plays an essential role in adipogenesis glucosehomeostasis and energy metabolismrdquo Cell Metabolism vol 9no 1 pp 77ndash87 2009

[86] F A Pereira Q Yuhong G Zhou M-J Tsai and S YTsai ldquoThe orphan nuclear receptor COUP-TFII is required forangiogenesis and heart developmentrdquo Genes and Developmentvol 13 no 8 pp 1037ndash1049 1999

[87] N Takamoto I Kurihara K Lee F J DeMayo M-J Tsai andS Y Tsai ldquoHaploinsufficiency of chicken ovalbumin upstreampromoter transcription factor II in female reproductionrdquoMolec-ular Endocrinology vol 19 no 9 pp 2299ndash2308 2005

[88] P Zhang M Bennoun C Gogard et al ldquoExpression of COUP-TFII in metabolic tissues during developmentrdquo Mechanisms ofDevelopment vol 119 no 1 pp 109ndash114 2002

16 ISRN Hepatology

[89] Z Xu S Yu C-H Hsu J Eguchi and E D Rosen ldquoTheorphan nuclear receptor chicken ovalbumin upstream pro-moter-transcription factor II is a critical regulator of adipogene-sisrdquoProceedings of theNationalAcademy of Sciences of theUnitedStates of America vol 105 no 7 pp 2421ndash2426 2008

[90] P Bardoux P Zhang D Flamez et al ldquoEssential role of chickenovalbumin upstreampromoter-transcription factor II in insulinsecretion and insulin sensitivity revealed by conditional geneknockoutrdquo Diabetes vol 54 no 5 pp 1357ndash1363 2005

[91] G Achatz B Holzl R Speckmayer C Hauser F Sandhoferand B Paulweber ldquoFunctional domains of the human orphanreceptor ARP-1COUP-TFII involved in active repression andtransrepressionrdquo Molecular and Cellular Biology vol 17 no 9pp 4914ndash4932 1997

[92] S A Kliewer K Umesono R A Heyman D J MangelsdorfJ A Dyck and R M Evans ldquoRetinoid X receptor-COUP-TFinteractionsmodulate retinoic acid signalingrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol89 no 4 pp 1448ndash1452 1992

[93] A J Cooney S Y Tsai BW OrsquoMalley andM-J Tsai ldquoChickenovalbumin upstreampromoter transcription factor (COUP-TF)dimers bind to different GGTCA response elements allowingCOUP-TF to repress hormonal induction of the vitamin D3thyroid hormone and retinoic acid receptorsrdquo Molecular andCellular Biology vol 12 no 9 pp 4153ndash4163 1992

[94] SW Kruse K Suino-Powell X E Zhou et al ldquoIdentification ofCOUP-TFII orphannuclear receptor as a retinoic acid-activatedreceptorrdquo PLoS Biology vol 6 no 9 Article ID e227 2008

[95] J P Berger T E Akiyama and P T Meinke ldquoPPARs thera-peutic targets for metabolic diseaserdquo Trends in PharmacologicalSciences vol 26 no 5 pp 244ndash251 2005

[96] JM Peters andF J Gonzalez ldquoSorting out the functional role(s)of peroxisome proliferator-activated receptor-120573120575 (PPAR120573120575)in cell proliferation and cancerrdquo Biochimica et Biophysica Actavol 1796 no 2 pp 230ndash241 2009

[97] A Tenenbaum and E Fisman ldquoBalanced pan-PPAR activatorbezafibrate in combination with statin comprehensive lipidscontrol and diabetes preventionrdquo Cardiovascular Diabetologyvol 11 no 1 article 140 2012

[98] O Braissant F Foufelle C Scotto M Dauca and W WahlildquoDifferential expression of peroxisome proliferator-activatedreceptors (PPARs) tissue distribution of PPAR-120572 -120573 and -120574 inthe adult ratrdquo Endocrinology vol 137 no 1 pp 354ndash366 1996

[99] H Higashiyama A N Billin Y Okamoto M Kinoshita andS Asano ldquoExpression profiling of Peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues usingtissue microarrayrdquo Histochemistry and Cell Biology vol 127 no5 pp 485ndash494 2007

[100] P S Jones R Savory P Barratt et al ldquoChromosomal local-isation inducibility tissue-specific expression and strain dif-ferences in three murine peroxisome-proliferator-activated-receptor genesrdquo European Journal of Biochemistry vol 233 no1 pp 219ndash226 1995

[101] S A Kliewer B M Forman B Blumberg et al ldquoDifferentialexpression and activation of a family of murine peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no15 pp 7355ndash7359 1994

[102] E E Girroir H E Hollingshead P He B Zhu G H Perdewand J M Peters ldquoQuantitative expression patterns of peroxi-some proliferator-activated receptor-120573120575 (PPAR120573120575) protein in

micerdquo Biochemical and Biophysical Research Communicationsvol 371 no 3 pp 456ndash461 2008

[103] P Escher O Braissant S Basu-Modak L Michalik W Wahliand B Desvergne ldquoRat PPARs quantitative analysis in adult rattissues and regulation in fasting and refeedingrdquo Endocrinologyvol 142 no 10 pp 4195ndash4202 2001

[104] D Auboeuf J Rieusset L Fajas et al ldquoTissue distributionand quantification of the expression of mRNAs of peroxi-some proliferator-activated receptors and liver X receptor-120572 inhumans no alteration in adipose tissue of obese and NIDDMpatientsrdquo Diabetes vol 46 no 8 pp 1319ndash1327 1997

[105] N ShawM Elholm andN Noy ldquoRetinoic acid is a high affinityselective ligand for the peroxisome proliferator-activated recep-tor 120573120575rdquo Journal of Biological Chemistry vol 278 no 43 pp41589ndash41592 2003

[106] G Wolf ldquoRetinoic acid as cause of cell proliferation or cellgrowth inhibition depending on activation of one of twodifferent nuclear receptorsrdquoNutrition Reviews vol 66 no 1 pp55ndash59 2008

[107] T T Schug D C Berry N S Shaw S N Travis and N NoyldquoOpposing effects of retinoic acid on cell growth result fromalternate activation of two different nuclear receptorsrdquo Cell vol129 no 4 pp 723ndash733 2007

[108] D C Berry and N Noy ldquoAll-trans-retinoic acid repressesobesity and insulin resistance by activating both peroxisomeproliferation-activated receptor 120573120575 and retinoic acid receptorrdquoMolecular and Cellular Biology vol 29 no 12 pp 3286ndash32962009

[109] D C Berry D DeSantis H Soltanian C M Croniger andN Noy ldquoRetinoic acid upregulates preadipocyte genes to blockadipogenesis and suppress diet-induced obesityrdquo Diabetes vol61 no 5 pp 1112ndash1121 2012

[110] M G Borland C Khozoie P P Albrecht et al ldquoStableover-expression of PPAR120573120575 and PPAR120574 to examine receptorsignaling in human HaCaT keratinocytesrdquo Cellular Signallingvol 23 no 12 pp 2039ndash2050 2011

[111] S E OrsquoSullivan and D A Kendall ldquoCannabinoid activationof peroxisome proliferator-activated receptors potential formodulation of inflammatory diseaserdquo Immunobiology vol 215no 8 pp 611ndash616 2010

[112] Z C Yan D Y Liu L L Zhang et al ldquoExercise reduces adiposetissue via cannabinoid receptor type 1 which is regulated byperoxisome proliferator-activated receptor-120575rdquo Biochemical andBiophysical Research Communications vol 354 no 2 pp 427ndash433 2007

[113] J D McGarry ldquoWhat if Minkowski had been ageusic Analternative angle on diabetesrdquo Science vol 258 no 5083 pp766ndash770 1992

[114] TMoore ldquoVitaminA and carotene the vitaminA reserve of theadult human being in health and diseaserdquo Biochemical Journalvol 31 no 1 pp 155ndash164 1937

[115] GWolfMD Lane and B C Johnson ldquoStudies on the functionof vitamin A in metabolismrdquo Journal of Biological Chemistryvol 225 no 2 pp 995ndash1008 1957

[116] Y Zhang R Li Y Li W Chen S Zhao and G Chen ldquoVitaminA status affects obesity development and hepatic expression ofkey genes for fuel metabolism in Zucker fatty ratsrdquoBiochemistryand Cell Biology vol 90 no 4 pp 548ndash557 2012

[117] M Singh V N Singh and T A Venkitasubramanian ldquoEarlyeffects of feeding excess vitamin A hepatic glycogen bloodlactic acid plasma nefa and glucose tolerance in ratsrdquo LifeSciences vol 7 no 5 pp 239ndash247 1968

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Hepatology 15

in the thyroid hormone receptorRXR heterodimerrdquoMolecularand Cellular Biology vol 22 no 16 pp 5782ndash5792 2002

[61] F M Sladek W Zhong E Lai and J E Darnell Jr ldquoLiver-enriched transcription factor HNF-4 is a novel member ofthe steroid hormone receptor superfamilyrdquo Genes and Develop-ment vol 4 no 12 pp 2353ndash2365 1990

[62] K Yamagata H Furuta N Oda et al ldquoMutations in thehepatocyte nuclear factor-4120572 gene inmaturity-onset diabetes ofthe young (MODY1)rdquo Nature vol 384 no 6608 pp 458ndash4601996

[63] M Stoffel and S ADuncan ldquoThematurity-onset diabetes of theyoung (MODY1) transcription factor HNF4120572 regulates expres-sion of genes required for glucose transport and metabolismrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 24 pp 13209ndash13214 1997

[64] M Lehto P-O Bitzen B Isomaa et al ldquoMutation in the HNF-4120572 gene affects insulin secretion and triglyceride metabolismrdquoDiabetes vol 48 no 2 pp 423ndash425 1999

[65] G P Hayhurst Y-H Lee G Lambert J M Ward and F JGonzalez ldquoHepatocyte nuclear factor 4120572 (Nuclear receptor 2A1)is essential formaintenance of hepatic gene expression and lipidhomeostasisrdquo Molecular and Cellular Biology vol 21 no 4 pp1393ndash1403 2001

[66] U Roth K Jungermann and T Kietzmann ldquoActivation ofglucokinase gene expression by hepatic nuclear factor 4120572 inprimary hepatocytesrdquo Biochemical Journal vol 365 no 1 pp223ndash228 2002

[67] S Mandard R Stienstra P Escher et al ldquoGlycogen synthase2 is a novel target gene of peroxisome proliferator-activatedreceptorsrdquo Cellular and Molecular Life Sciences vol 64 no 9pp 1145ndash1157 2007

[68] F Rajas A Gautier I Bady S Montano and G MithieuxldquoPolyunsaturated fatty acyl coenzyme a suppress the glucose-6-phosphatase promoter activity bymodulating the DNA bindingof hepatocyte nuclear factor 4120572rdquo Journal of Biological Chemistryvol 277 no 18 pp 15736ndash15744 2002

[69] B Viollet A Kahn and M Raymondjean ldquoProtein kinase A-dependent phosphorylation modulates DNA-binding activityof hepatocyte nuclear factor 4rdquoMolecular and Cellular Biologyvol 17 no 8 pp 4208ndash4219 1997

[70] L Palanker J M Tennessen G Lam and C S Thum-mel ldquoDrosophila HNF4 regulates lipid mobilization and 120573-oxidationrdquo Cell Metabolism vol 9 no 3 pp 228ndash239 2009

[71] A Miura K Yamagata M Kakei et al ldquoHepatocyte nuclearfactor-4120572 is essential for glucose-stimulated insulin secretion bypancreatic 120573-cellsrdquo Journal of Biological Chemistry vol 281 no8 pp 5246ndash5257 2006

[72] R Bartoov-Shifman R Hertz H Wang C B Wollheim JBar-Tana and M D Walker ldquoActivation of the insulin genepromoter through a direct effect of hepatocyte nuclear factor4120572rdquo Journal of Biological Chemistry vol 277 no 29 pp 25914ndash25919 2002

[73] H Wang P Maechler P A Antinozzi K A Hagenfeldt andC B Wollheim ldquoHepatocyte nuclear factor 4120572 regulates theexpression of pancreatic 120573-cell genes implicated in glucosemetabolism and nutrient-induced insulin secretionrdquo Journal ofBiological Chemistry vol 275 no 46 pp 35953ndash35959 2000

[74] K Reue T Leff and J L Breslow ldquoHuman apolipoproteinCIII gene expression is regulated by positive and negative cis-acting elements and tissue-specific protein factorsrdquo Journal ofBiological Chemistry vol 263 no 14 pp 6857ndash6864 1988

[75] T Leff K Reue A Melian H Culver and J L BreslowldquoA regulatory element in the apoCIII promoter that directshepatic specific transcription binds to proteins in expressingand nonexpressing cell typesrdquo Journal of Biological Chemistryvol 264 no 27 pp 16132ndash16137 1989

[76] S N Lavrentiadou M Hadzopoulou-Cladaras D Kardassisand V I Zannis ldquoBinding specificity and modulation of thehuman apocIII promoter activity by heterodimers of ligand-dependent nuclear receptorsrdquo Biochemistry vol 38 no 3 pp964ndash975 1999

[77] T R Magee Y Cai M E El-Houseini J Locker and Y-JY Wan ldquoRetinoic acid mediates down-regulation of the 120572-fetoprotein gene through decreased expression of hepatocytenuclear factorsrdquo Journal of Biological Chemistry vol 273 no 45pp 30024ndash30032 1998

[78] A Qian Y Cai T R Magee and Y J Y Wan ldquoIdentificationof retinoic acid-responsive elements on the HNF1alpha andHNF4alpha genesrdquo Biochemical and Biophysical Research Com-munications vol 276 no 3 pp 837ndash842 2000

[79] H Nakshatri and P Chambon ldquoThe directly repeatedRG(GT)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites forRAR RXR HNF-4 and ARP-1 homo- and heterodimersrdquoJournal of Biological Chemistry vol 269 no 2 pp 890ndash9021994

[80] T Makita G Hernandez-Hoyos T H-P Chen H Wu E VRothenberg and H M Sucov ldquoA developmental transition indefinitive erythropoiesis erythropoietin expression is sequen-tially regulated by retinoic acid receptors andHNF4rdquoGenes andDevelopment vol 15 no 7 pp 889ndash901 2001

[81] T I Kambe J Tada-Kambe Y Kuge Y Yamaguchi-Iwai MNagao and R Sasaki ldquoRetinoic acid stimulates erythropoietingene transcription in embryonal carcinoma cells through thedirect repeat of a steroidthyroid hormone receptor responseelement half-site in the hypoxia-response enhancerrdquo Blood vol96 no 9 pp 3265ndash3271 2000

[82] F-J Lin J Qin K Tang S Y Tsai and M-J Tsai ldquoCoup drsquoEtatan orphan takes controlrdquo Endocrine Reviews vol 32 no 3 pp404ndash421 2011

[83] L-H Wang S Y Tsai R G Cook W G Beattie M-J Tsaiand BW OrsquoMalley ldquoCOUP transcription factor is a member ofthe steroid receptor superfamilyrdquoNature vol 340 no 6229 pp163ndash166 1989

[84] X Leng A J Cooney S Y Tsai and M-J Tsai ldquoMolecularmechanisms of COUP-TF-mediated transcriptional repressionevidence for transrepression and active repressionrdquo Molecularand Cellular Biology vol 16 no 5 pp 2332ndash2340 1996

[85] L Li X Xie J Qin et al ldquoThe nuclear orphan receptorCOUP-TFII plays an essential role in adipogenesis glucosehomeostasis and energy metabolismrdquo Cell Metabolism vol 9no 1 pp 77ndash87 2009

[86] F A Pereira Q Yuhong G Zhou M-J Tsai and S YTsai ldquoThe orphan nuclear receptor COUP-TFII is required forangiogenesis and heart developmentrdquo Genes and Developmentvol 13 no 8 pp 1037ndash1049 1999

[87] N Takamoto I Kurihara K Lee F J DeMayo M-J Tsai andS Y Tsai ldquoHaploinsufficiency of chicken ovalbumin upstreampromoter transcription factor II in female reproductionrdquoMolec-ular Endocrinology vol 19 no 9 pp 2299ndash2308 2005

[88] P Zhang M Bennoun C Gogard et al ldquoExpression of COUP-TFII in metabolic tissues during developmentrdquo Mechanisms ofDevelopment vol 119 no 1 pp 109ndash114 2002

16 ISRN Hepatology

[89] Z Xu S Yu C-H Hsu J Eguchi and E D Rosen ldquoTheorphan nuclear receptor chicken ovalbumin upstream pro-moter-transcription factor II is a critical regulator of adipogene-sisrdquoProceedings of theNationalAcademy of Sciences of theUnitedStates of America vol 105 no 7 pp 2421ndash2426 2008

[90] P Bardoux P Zhang D Flamez et al ldquoEssential role of chickenovalbumin upstreampromoter-transcription factor II in insulinsecretion and insulin sensitivity revealed by conditional geneknockoutrdquo Diabetes vol 54 no 5 pp 1357ndash1363 2005

[91] G Achatz B Holzl R Speckmayer C Hauser F Sandhoferand B Paulweber ldquoFunctional domains of the human orphanreceptor ARP-1COUP-TFII involved in active repression andtransrepressionrdquo Molecular and Cellular Biology vol 17 no 9pp 4914ndash4932 1997

[92] S A Kliewer K Umesono R A Heyman D J MangelsdorfJ A Dyck and R M Evans ldquoRetinoid X receptor-COUP-TFinteractionsmodulate retinoic acid signalingrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol89 no 4 pp 1448ndash1452 1992

[93] A J Cooney S Y Tsai BW OrsquoMalley andM-J Tsai ldquoChickenovalbumin upstreampromoter transcription factor (COUP-TF)dimers bind to different GGTCA response elements allowingCOUP-TF to repress hormonal induction of the vitamin D3thyroid hormone and retinoic acid receptorsrdquo Molecular andCellular Biology vol 12 no 9 pp 4153ndash4163 1992

[94] SW Kruse K Suino-Powell X E Zhou et al ldquoIdentification ofCOUP-TFII orphannuclear receptor as a retinoic acid-activatedreceptorrdquo PLoS Biology vol 6 no 9 Article ID e227 2008

[95] J P Berger T E Akiyama and P T Meinke ldquoPPARs thera-peutic targets for metabolic diseaserdquo Trends in PharmacologicalSciences vol 26 no 5 pp 244ndash251 2005

[96] JM Peters andF J Gonzalez ldquoSorting out the functional role(s)of peroxisome proliferator-activated receptor-120573120575 (PPAR120573120575)in cell proliferation and cancerrdquo Biochimica et Biophysica Actavol 1796 no 2 pp 230ndash241 2009

[97] A Tenenbaum and E Fisman ldquoBalanced pan-PPAR activatorbezafibrate in combination with statin comprehensive lipidscontrol and diabetes preventionrdquo Cardiovascular Diabetologyvol 11 no 1 article 140 2012

[98] O Braissant F Foufelle C Scotto M Dauca and W WahlildquoDifferential expression of peroxisome proliferator-activatedreceptors (PPARs) tissue distribution of PPAR-120572 -120573 and -120574 inthe adult ratrdquo Endocrinology vol 137 no 1 pp 354ndash366 1996

[99] H Higashiyama A N Billin Y Okamoto M Kinoshita andS Asano ldquoExpression profiling of Peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues usingtissue microarrayrdquo Histochemistry and Cell Biology vol 127 no5 pp 485ndash494 2007

[100] P S Jones R Savory P Barratt et al ldquoChromosomal local-isation inducibility tissue-specific expression and strain dif-ferences in three murine peroxisome-proliferator-activated-receptor genesrdquo European Journal of Biochemistry vol 233 no1 pp 219ndash226 1995

[101] S A Kliewer B M Forman B Blumberg et al ldquoDifferentialexpression and activation of a family of murine peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no15 pp 7355ndash7359 1994

[102] E E Girroir H E Hollingshead P He B Zhu G H Perdewand J M Peters ldquoQuantitative expression patterns of peroxi-some proliferator-activated receptor-120573120575 (PPAR120573120575) protein in

micerdquo Biochemical and Biophysical Research Communicationsvol 371 no 3 pp 456ndash461 2008

[103] P Escher O Braissant S Basu-Modak L Michalik W Wahliand B Desvergne ldquoRat PPARs quantitative analysis in adult rattissues and regulation in fasting and refeedingrdquo Endocrinologyvol 142 no 10 pp 4195ndash4202 2001

[104] D Auboeuf J Rieusset L Fajas et al ldquoTissue distributionand quantification of the expression of mRNAs of peroxi-some proliferator-activated receptors and liver X receptor-120572 inhumans no alteration in adipose tissue of obese and NIDDMpatientsrdquo Diabetes vol 46 no 8 pp 1319ndash1327 1997

[105] N ShawM Elholm andN Noy ldquoRetinoic acid is a high affinityselective ligand for the peroxisome proliferator-activated recep-tor 120573120575rdquo Journal of Biological Chemistry vol 278 no 43 pp41589ndash41592 2003

[106] G Wolf ldquoRetinoic acid as cause of cell proliferation or cellgrowth inhibition depending on activation of one of twodifferent nuclear receptorsrdquoNutrition Reviews vol 66 no 1 pp55ndash59 2008

[107] T T Schug D C Berry N S Shaw S N Travis and N NoyldquoOpposing effects of retinoic acid on cell growth result fromalternate activation of two different nuclear receptorsrdquo Cell vol129 no 4 pp 723ndash733 2007

[108] D C Berry and N Noy ldquoAll-trans-retinoic acid repressesobesity and insulin resistance by activating both peroxisomeproliferation-activated receptor 120573120575 and retinoic acid receptorrdquoMolecular and Cellular Biology vol 29 no 12 pp 3286ndash32962009

[109] D C Berry D DeSantis H Soltanian C M Croniger andN Noy ldquoRetinoic acid upregulates preadipocyte genes to blockadipogenesis and suppress diet-induced obesityrdquo Diabetes vol61 no 5 pp 1112ndash1121 2012

[110] M G Borland C Khozoie P P Albrecht et al ldquoStableover-expression of PPAR120573120575 and PPAR120574 to examine receptorsignaling in human HaCaT keratinocytesrdquo Cellular Signallingvol 23 no 12 pp 2039ndash2050 2011

[111] S E OrsquoSullivan and D A Kendall ldquoCannabinoid activationof peroxisome proliferator-activated receptors potential formodulation of inflammatory diseaserdquo Immunobiology vol 215no 8 pp 611ndash616 2010

[112] Z C Yan D Y Liu L L Zhang et al ldquoExercise reduces adiposetissue via cannabinoid receptor type 1 which is regulated byperoxisome proliferator-activated receptor-120575rdquo Biochemical andBiophysical Research Communications vol 354 no 2 pp 427ndash433 2007

[113] J D McGarry ldquoWhat if Minkowski had been ageusic Analternative angle on diabetesrdquo Science vol 258 no 5083 pp766ndash770 1992

[114] TMoore ldquoVitaminA and carotene the vitaminA reserve of theadult human being in health and diseaserdquo Biochemical Journalvol 31 no 1 pp 155ndash164 1937

[115] GWolfMD Lane and B C Johnson ldquoStudies on the functionof vitamin A in metabolismrdquo Journal of Biological Chemistryvol 225 no 2 pp 995ndash1008 1957

[116] Y Zhang R Li Y Li W Chen S Zhao and G Chen ldquoVitaminA status affects obesity development and hepatic expression ofkey genes for fuel metabolism in Zucker fatty ratsrdquoBiochemistryand Cell Biology vol 90 no 4 pp 548ndash557 2012

[117] M Singh V N Singh and T A Venkitasubramanian ldquoEarlyeffects of feeding excess vitamin A hepatic glycogen bloodlactic acid plasma nefa and glucose tolerance in ratsrdquo LifeSciences vol 7 no 5 pp 239ndash247 1968

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

16 ISRN Hepatology

[89] Z Xu S Yu C-H Hsu J Eguchi and E D Rosen ldquoTheorphan nuclear receptor chicken ovalbumin upstream pro-moter-transcription factor II is a critical regulator of adipogene-sisrdquoProceedings of theNationalAcademy of Sciences of theUnitedStates of America vol 105 no 7 pp 2421ndash2426 2008

[90] P Bardoux P Zhang D Flamez et al ldquoEssential role of chickenovalbumin upstreampromoter-transcription factor II in insulinsecretion and insulin sensitivity revealed by conditional geneknockoutrdquo Diabetes vol 54 no 5 pp 1357ndash1363 2005

[91] G Achatz B Holzl R Speckmayer C Hauser F Sandhoferand B Paulweber ldquoFunctional domains of the human orphanreceptor ARP-1COUP-TFII involved in active repression andtransrepressionrdquo Molecular and Cellular Biology vol 17 no 9pp 4914ndash4932 1997

[92] S A Kliewer K Umesono R A Heyman D J MangelsdorfJ A Dyck and R M Evans ldquoRetinoid X receptor-COUP-TFinteractionsmodulate retinoic acid signalingrdquoProceedings of theNational Academy of Sciences of theUnited States of America vol89 no 4 pp 1448ndash1452 1992

[93] A J Cooney S Y Tsai BW OrsquoMalley andM-J Tsai ldquoChickenovalbumin upstreampromoter transcription factor (COUP-TF)dimers bind to different GGTCA response elements allowingCOUP-TF to repress hormonal induction of the vitamin D3thyroid hormone and retinoic acid receptorsrdquo Molecular andCellular Biology vol 12 no 9 pp 4153ndash4163 1992

[94] SW Kruse K Suino-Powell X E Zhou et al ldquoIdentification ofCOUP-TFII orphannuclear receptor as a retinoic acid-activatedreceptorrdquo PLoS Biology vol 6 no 9 Article ID e227 2008

[95] J P Berger T E Akiyama and P T Meinke ldquoPPARs thera-peutic targets for metabolic diseaserdquo Trends in PharmacologicalSciences vol 26 no 5 pp 244ndash251 2005

[96] JM Peters andF J Gonzalez ldquoSorting out the functional role(s)of peroxisome proliferator-activated receptor-120573120575 (PPAR120573120575)in cell proliferation and cancerrdquo Biochimica et Biophysica Actavol 1796 no 2 pp 230ndash241 2009

[97] A Tenenbaum and E Fisman ldquoBalanced pan-PPAR activatorbezafibrate in combination with statin comprehensive lipidscontrol and diabetes preventionrdquo Cardiovascular Diabetologyvol 11 no 1 article 140 2012

[98] O Braissant F Foufelle C Scotto M Dauca and W WahlildquoDifferential expression of peroxisome proliferator-activatedreceptors (PPARs) tissue distribution of PPAR-120572 -120573 and -120574 inthe adult ratrdquo Endocrinology vol 137 no 1 pp 354ndash366 1996

[99] H Higashiyama A N Billin Y Okamoto M Kinoshita andS Asano ldquoExpression profiling of Peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues usingtissue microarrayrdquo Histochemistry and Cell Biology vol 127 no5 pp 485ndash494 2007

[100] P S Jones R Savory P Barratt et al ldquoChromosomal local-isation inducibility tissue-specific expression and strain dif-ferences in three murine peroxisome-proliferator-activated-receptor genesrdquo European Journal of Biochemistry vol 233 no1 pp 219ndash226 1995

[101] S A Kliewer B M Forman B Blumberg et al ldquoDifferentialexpression and activation of a family of murine peroxisomeproliferator-activated receptorsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 91 no15 pp 7355ndash7359 1994

[102] E E Girroir H E Hollingshead P He B Zhu G H Perdewand J M Peters ldquoQuantitative expression patterns of peroxi-some proliferator-activated receptor-120573120575 (PPAR120573120575) protein in

micerdquo Biochemical and Biophysical Research Communicationsvol 371 no 3 pp 456ndash461 2008

[103] P Escher O Braissant S Basu-Modak L Michalik W Wahliand B Desvergne ldquoRat PPARs quantitative analysis in adult rattissues and regulation in fasting and refeedingrdquo Endocrinologyvol 142 no 10 pp 4195ndash4202 2001

[104] D Auboeuf J Rieusset L Fajas et al ldquoTissue distributionand quantification of the expression of mRNAs of peroxi-some proliferator-activated receptors and liver X receptor-120572 inhumans no alteration in adipose tissue of obese and NIDDMpatientsrdquo Diabetes vol 46 no 8 pp 1319ndash1327 1997

[105] N ShawM Elholm andN Noy ldquoRetinoic acid is a high affinityselective ligand for the peroxisome proliferator-activated recep-tor 120573120575rdquo Journal of Biological Chemistry vol 278 no 43 pp41589ndash41592 2003

[106] G Wolf ldquoRetinoic acid as cause of cell proliferation or cellgrowth inhibition depending on activation of one of twodifferent nuclear receptorsrdquoNutrition Reviews vol 66 no 1 pp55ndash59 2008

[107] T T Schug D C Berry N S Shaw S N Travis and N NoyldquoOpposing effects of retinoic acid on cell growth result fromalternate activation of two different nuclear receptorsrdquo Cell vol129 no 4 pp 723ndash733 2007

[108] D C Berry and N Noy ldquoAll-trans-retinoic acid repressesobesity and insulin resistance by activating both peroxisomeproliferation-activated receptor 120573120575 and retinoic acid receptorrdquoMolecular and Cellular Biology vol 29 no 12 pp 3286ndash32962009

[109] D C Berry D DeSantis H Soltanian C M Croniger andN Noy ldquoRetinoic acid upregulates preadipocyte genes to blockadipogenesis and suppress diet-induced obesityrdquo Diabetes vol61 no 5 pp 1112ndash1121 2012

[110] M G Borland C Khozoie P P Albrecht et al ldquoStableover-expression of PPAR120573120575 and PPAR120574 to examine receptorsignaling in human HaCaT keratinocytesrdquo Cellular Signallingvol 23 no 12 pp 2039ndash2050 2011

[111] S E OrsquoSullivan and D A Kendall ldquoCannabinoid activationof peroxisome proliferator-activated receptors potential formodulation of inflammatory diseaserdquo Immunobiology vol 215no 8 pp 611ndash616 2010

[112] Z C Yan D Y Liu L L Zhang et al ldquoExercise reduces adiposetissue via cannabinoid receptor type 1 which is regulated byperoxisome proliferator-activated receptor-120575rdquo Biochemical andBiophysical Research Communications vol 354 no 2 pp 427ndash433 2007

[113] J D McGarry ldquoWhat if Minkowski had been ageusic Analternative angle on diabetesrdquo Science vol 258 no 5083 pp766ndash770 1992

[114] TMoore ldquoVitaminA and carotene the vitaminA reserve of theadult human being in health and diseaserdquo Biochemical Journalvol 31 no 1 pp 155ndash164 1937

[115] GWolfMD Lane and B C Johnson ldquoStudies on the functionof vitamin A in metabolismrdquo Journal of Biological Chemistryvol 225 no 2 pp 995ndash1008 1957

[116] Y Zhang R Li Y Li W Chen S Zhao and G Chen ldquoVitaminA status affects obesity development and hepatic expression ofkey genes for fuel metabolism in Zucker fatty ratsrdquoBiochemistryand Cell Biology vol 90 no 4 pp 548ndash557 2012

[117] M Singh V N Singh and T A Venkitasubramanian ldquoEarlyeffects of feeding excess vitamin A hepatic glycogen bloodlactic acid plasma nefa and glucose tolerance in ratsrdquo LifeSciences vol 7 no 5 pp 239ndash247 1968

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Hepatology 17

[118] M L Cardenas A Cornish-Bowden and T Ureta ldquoEvolutionand regulatory role of the hexokinasesrdquoBiochimica et BiophysicaActa vol 1401 no 3 pp 242ndash264 1998

[119] P B Iynedjian ldquoMammalian glucokinase and its generdquo Bio-chemical Journal vol 293 no 1 pp 1ndash13 1993

[120] M A Magnuson T L Andreone R L Printz S Koch and DK Granner ldquoRat glucokinase gene structure and regulation byinsulinrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 86 no 13 pp 4838ndash4842 1989

[121] F M Matschinsky M A Magnuson D Zelent et al ldquoThenetwork of glucokinase-expressing cells in glucose homeostasisand the potential of glucokinase activators for diabetes therapyrdquoDiabetes vol 55 no 1 pp 1ndash12 2006

[122] P Froguel H Zouali N Vionnet et al ldquoFamilial hyperglycemiadue to mutations in glucokinase definition of a subtype ofdiabetes mellitusrdquo The New England Journal of Medicine vol328 no 10 pp 697ndash702 1993

[123] M Gidh-Jain J Takeda L Z Xu et al ldquoGlucokinase muta-tions associated with non-insulin-dependent (type 2) diabetesmellitus have decreased enzymatic activity implications forstructurefunction relationshipsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 90 no5 pp 1932ndash1936 1993

[124] E Vinuela M Salas and A Sols ldquoGlucokinase and hexokinasein liver in relation to glycogen synthesisrdquo The Journal ofBiological Chemistry vol 238 pp 1175ndash1177 1963

[125] P B Iynedjian G Mobius and H J Seitz ldquoTissue-specificexpression of glucokinase identification of the gene product inliver and pancreatic isletsrdquo Proceedings of the National Academyof Sciences of theUnited States of America vol 83 no 7 pp 1998ndash2001 1986

[126] Y Liang T L Jetton E C Zimmerman H Najafi F MMatschinsky and M A Magnuson ldquoEffects of alternate RNAsplicing on glucokinase isoform activities in the pancreatic isletliver and pituitaryrdquo Journal of Biological Chemistry vol 266 no11 pp 6999ndash7007 1991

[127] E van Schaftingen M Detheux and M V da Cunha ldquoShort-term control of glucokinase activity role of a regulatoryproteinrdquo FASEB Journal vol 8 no 6 pp 414ndash419 1994

[128] P Ekman and E Nilsson ldquoPhosphorylation of glucokinasefrom rat liver in vitro by protein kinase A with a concomitantdecrease of its activityrdquo Archives of Biochemistry and Biophysicsvol 261 no 2 pp 275ndash282 1988

[129] M J Munoz-Alonso G Guillemain N Kassis J Girard A-F Burnol and A Leturque ldquoA novel cytosolic dual specificityphosphatase interacting with glucokinase increases glucosephosphorylation raterdquo Journal of Biological Chemistry vol 275no 42 pp 32406ndash32412 2000

[130] P B Iynedjian P-R Pilot T Nouspikel et al ldquoDifferentialexpression and regulation of the glucokinase gene in liver andislets of Langerhansrdquo Proceedings of the National Academy ofSciences of the United States of America vol 86 no 20 pp 7838ndash7842 1989

[131] M A Magnuson and K D Shelton ldquoAn alternate promoter inthe glucokinase gene is active in the pancreatic 120573 cellrdquo Journalof Biological Chemistry vol 264 no 27 pp 15936ndash15942 1989

[132] T L Jetton Y Liang C C Pettepher et al ldquoAnalysis ofupstream glucokinase promoter activity in transgenic mice andidentification of glucokinase in rare neuroendocrine cells in thebrain and gutrdquo Journal of Biological Chemistry vol 269 no 5pp 3641ndash3654 1994

[133] P B Iynedjian A Gjinovci and A E Renold ldquoStimulation byinsulin of glucokinase gene transcription in liver of diabeticratsrdquo Journal of Biological Chemistry vol 263 no 2 pp 740ndash744 1988

[134] P B Iynedjian D Jotterand T Nouspikel M Asfari and P-RPilot ldquoTranscriptional induction of glucokinase gene by insulinin cultured liver cells and its repression by the glucagon-cAMPsystemrdquo Journal of Biological Chemistry vol 264 no 36 pp21824ndash21829 1989

[135] W Sibrowski and H J Seitz ldquoRapid action of insulin and cyclicAMP in the regulation of functional messenger RNA coding forglucokinase in rat liverrdquo Journal of Biological Chemistry vol 259no 1 pp 343ndash346 1984

[136] T Noguchi M Takenaka K Yamada T Matsuda MHashimoto and T Tanaka ldquoCharacterization of the 51015840 flankingregion of rat glucokinase generdquo Biochemical and BiophysicalResearch Communications vol 164 no 3 pp 1247ndash1252 1989

[137] G Chen Y Zhang D Lu N-Q Li and A C Ross ldquoRetinoidssynergize with insulin to induce hepatic Gck expressionrdquoBiochemical Journal vol 419 no 3 pp 645ndash653 2009

[138] P B Iynedjian SMarieHWangAGjinovci andKNazaryanldquoLiver-specific enhancer of the glucokinase generdquo Journal ofBiological Chemistry vol 271 no 46 pp 29113ndash29120 1996

[139] G Cabrera-Valladares F M Matschinsky J Wang and CFernandez-Mejia ldquoEffect of retinoic acid on glucokinase activ-ity and gene expression in neonatal and adult cultured hepato-cytesrdquo Life Sciences vol 68 no 25 pp 2813ndash2824 2001

[140] J-F Decaux M Juanes P Bossard and J Girard ldquoEffectsof triiodothyronine and retinoic acid on glucokinase geneexpression in neonatal rat hepatocytesrdquoMolecular and CellularEndocrinology vol 130 no 1-2 pp 61ndash67 1997

[141] R W Hanson and A J Garber ldquoPhosphoenolpyruvate car-boxykinase I Its role in gluconeogenesisrdquo The American Jour-nal of Clinical Nutrition vol 25 no 10 pp 1010ndash1021 1972

[142] R W Hanson and L Reshef ldquoRegulation of phosphoenolpyru-vate carboxykinase (GTP) gene expressionrdquo Annual Review ofBiochemistry vol 66 pp 581ndash611 1997

[143] R M OrsquoBrien R L Printz N Halmi J J Tiesinga andD K Granner ldquoStructural and functional analysis of thehuman phosphoenolpyruvate carboxykinase gene promoterrdquoBiochimica et BiophysicaActa vol 1264 no 3 pp 284ndash288 1995

[144] R W Hanson and L Reshef ldquoGlyceroneogenesis revisitedrdquoBiochimie vol 85 no 12 pp 1199ndash1205 2003

[145] R M OrsquoBrien and D K Granner ldquoRegulation of gene expres-sion by insulinrdquo Physiological Reviews vol 76 no 4 pp 1109ndash1161 1996

[146] M Benvenisty and L Reshef ldquoDevelopmental acquisition ofDNase I sensitivity of the phosphoenolpyruvate carboxykinase(GTP) gene in rat liverrdquo Proceedings of the National Academy ofSciences of the United States of America vol 84 no 5 pp 1132ndash1136 1987

[147] W J Roesler G R Vandenbark and R W Hanson ldquoIdentifi-cation of multiple protein binding domains in the promoter-regulatory region of the phosphoenolpyruvate carboxykinase(GTP) generdquo Journal of Biological Chemistry vol 264 no 16pp 9657ndash9664 1989

[148] E Imai J N Miner J A Mitchell K R Yamamoto and DK Granner ldquoGlucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phospho-enolpyruvate carboxykinase gene to glucocorticoidsrdquo Journal ofBiological Chemistry vol 268 no 8 pp 5353ndash5356 1993

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

18 ISRN Hepatology

[149] R K Hall F M Sladek and D K Granner ldquoThe orphanreceptors COUP-TF and HNF-4 serve as accessory factorsrequired for induction of phosphoenolpyruvate carboxyki-nase gene transcription by glucocorticoidsrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 92 no 2 pp 412ndash416 1995

[150] T Kucera M Waltner-Law D K Scott R Prasad and D KGranner ldquoA point mutation of the AF2 transactivation domainof the glucocorticoid receptor disrupts its interaction withsteroid receptor coactivator 1rdquo Journal of Biological Chemistryvol 277 no 29 pp 26098ndash26102 2002

[151] M J Nyirenda R S Lindsay C J Kenyon A Burchell and J RSeckl ldquoGlucocorticoid exposure in late gestation permanentlyprograms rat hepatic phosphoenolpyruvate carboxykinase andglucocorticoid receptor expression and causes glucose intoler-ance in adult offspringrdquo Journal of Clinical Investigation vol 101no 10 pp 2174ndash2181 1998

[152] D K Scott P-E Stromstedt J-C Wang and D K GrannerldquoFurther characterization of the glucocorticoid response unit inthe phosphoenolpyruvate carboxykinase gene The role of theglucocorticoid receptor-binding sitesrdquo Molecular Endocrinol-ogy vol 12 no 4 pp 482ndash491 1998

[153] T Sugiyama D K Scott J-C Wang and D K GrannerldquoStructural requirements of the glucocorticoid and retinoic acidresponse units in the phosphoenolpyruvate carboxykinase genepromoterrdquo Molecular Endocrinology vol 12 no 10 pp 1487ndash1498 1998

[154] P C Lucas B M Forman H H Samuels and D K GrannerldquoSpecificity of a retinoic acid response element in the phos-phoenolpyruvate carboxykinase gene promoter consequencesof both retinoic acid and thyroid hormone receptor bindingrdquoMolecular and Cellular Biology vol 11 no 10 pp 5164ndash51701991

[155] P C Lucas R M OrsquoBrien J A Mitchell et al ldquoA retinoicacid response element is part of a pleiotropic domain in thephosphoenolpyruvate carboxykinase generdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 88 no 6 pp 2184ndash2188 1991

[156] D K Scott J A Mitchell and D K Granner ldquoIdentificationand characterization of a second retinoic acid response elementin the phosphoenolpyruvate carboxykinase gene promoterrdquoJournal of Biological Chemistry vol 271 no 11 pp 6260ndash62641996

[157] D-J Shin D P Odom K B Scribner S Ghoshal and MM McGrane ldquoRetinoid regulation of the phosphoenolpyruvatecarboxykinase gene in liverrdquoMolecular and Cellular Endocrinol-ogy vol 195 no 1-2 pp 39ndash54 2002

[158] M Giralt E A Park A L Gurney J Liu P Hakimi and R WHanson ldquoIdentification of a thyroid hormone response elementin the phosphoenolpyruvate carboxykinase (GTP) gene Evi-dence for synergistic interaction between thyroid hormone andcAMP cis-regulatory elementsrdquo Journal of Biological Chemistryvol 266 no 32 pp 21991ndash21996 1991

[159] B A Laffitte L C Chao J Li et al ldquoActivation of liverX receptor improves glucose tolerance through coordinateregulation of glucose metabolism in liver and adipose tissuerdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 9 pp 5419ndash5424 2003

[160] R K Hall T Yamasaki T Kucera MWaltner-Law R OrsquoBrienand D K Granner ldquoRegulation of phosphoenolpyruvate car-boxykinase and insulin-like growth factor-binding protein-1gene expression by insulin The role of winged helixforkhead

proteinsrdquo Journal of Biological Chemistry vol 275 no 39 pp30169ndash30175 2000

[161] E A Park A L Gurney S E Nizielski et al ldquoRelative rolesof CCAATenhancer-binding protein 120573 and cAMP regulatoryelement-binding protein in controlling transcription of thegene for phosphoenolpyruvate carboxykinase (GTP)rdquo Journalof Biological Chemistry vol 268 no 1 pp 613ndash619 1993

[162] K Chakravarty P Leahy D Becard et al ldquoSterol regulatoryelement-binding protein-1cmimics the negative effect of insulinon phosphoenolpyruvate carboxykinase (GTP) gene transcrip-tionrdquo Journal of Biological Chemistry vol 276 no 37 pp 34816ndash34823 2001

[163] K Chakravarty S-Y Wu C-M Chiang D Samols and R WHanson ldquoSREBP-1c and Sp1 interact to regulate transcription ofthe gene for phosphoenolpyruvate carboxykinase (GTP) in theliverrdquo Journal of Biological Chemistry vol 279 no 15 pp 15385ndash15395 2004

[164] P Leahy D R Crawford G Grossman R M Gronostajskiand R W Hanson ldquoCREB binding protein coordinates thefunction of multiple transcription factors including nuclearfactor I to regulate phosphoenolpyruvate carboxykinase (GTP)gene transcriptionrdquo Journal of Biological Chemistry vol 274 no13 pp 8813ndash8822 1999

[165] J M Stafford M Waltner-Law and D K Granner ldquoRoleof accessory factors and steroid receptor coactivator 1 in theregulation of phosphoenolpyruvate carboxykinase gene tran-scription by glucocorticoidsrdquo Journal of Biological Chemistryvol 276 no 6 pp 3811ndash3819 2001

[166] J C Yoon P Puigserver G Chen et al ldquoControl of hepaticgluconeogenesis through the transcriptional coaotivator PGC-1rdquo Nature vol 413 no 6852 pp 131ndash138 2001

[167] D-J Shin A Tao and M M McGrane ldquoEffects of vitaminA deficiency and retinoic acid treatment on expression of aphosphoenolpyruvate carboxykinase bovine growth hormonegene in transgenic micerdquo Biochemical and Biophysical ResearchCommunications vol 213 no 2 pp 706ndash714 1995

[168] K B Scribner and M M McGrane ldquoRNA polymerase II asso-ciation with the phosphoenolpyruvate carboxykinase (PEPCK)promoter is reduced in vitamin A-deficient micerdquo Journal ofNutrition vol 133 no 12 pp 4112ndash4117 2003

[169] K B Scribner D P Odom and M M McGrane ldquoVitamin Astatus in mice affects the histone code of the phosphoenolpyru-vate carboxykinase gene in liverrdquo Journal of Nutrition vol 135no 12 pp 2774ndash2779 2005

[170] K B Scribner D P Odom and M M McGrane ldquoNuclearreceptor binding to the retinoic acid response elements of thephosphoenolpyruvate carboxykinase gene in vivo effects ofvitamin A deficiencyrdquo Journal of Nutritional Biochemistry vol18 no 3 pp 206ndash214 2007

[171] G Chen ldquoLiver lipid molecules induce PEPCK-C gene tran-scription and attenuate insulin actionrdquo Biochemical and Bio-physical Research Communications vol 361 no 3 pp 805ndash8102007

[172] Y Zhang R LiW Chen Y Li andG Chen ldquoRetinoids inducedPck1 expression and attenuated insulin-mediated suppression ofits expression via activation of retinoic acid receptor in primaryrat hepatocytesrdquo Molecular and Cellular Biochemistry vol 355no 1-2 pp 1ndash8 2011

[173] S M OrsquoByrne andW S Blaner ldquoRetinol and retinyl esters bio-chemistry and physiology thematic review series fat-solublevitamins vitamin Ardquo Journal of Lipid Research vol 54 no 7pp 1731ndash1743 2013

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Hepatology 19

[174] T E Graham Q Yang M Bluher et al ldquoRetinol-bindingprotein 4 and insulin resistance in lean obese and diabeticsubjectsrdquoTheNew England Journal of Medicine vol 354 no 24pp 2552ndash2563 2006

[175] Q Yang T E Graham N Mody et al ldquoSerum retinol bindingprotein 4 contributes to insulin resistance in obesity and type 2diabetesrdquo Nature vol 436 no 7049 pp 356ndash362 2005

[176] T K Basu W J Tze and J Leichter ldquoSerum vitamin Aand retinol-binding protein in patients with insulin-dependentdiabetes mellitusrdquo The American Journal of Clinical Nutritionvol 50 no 2 pp 329ndash331 1989

[177] P J Tuitoek S Ziari A T C Tsin R V Rajotte M Suh and TK Basu ldquoStreptozotocin-induced diabetes in rats is associatedwith impaired metabolic availability of vitamin A (retinol)rdquoBritish Journal of Nutrition vol 75 no 4 pp 615ndash622 1996

[178] A Motani Z Wang M Conn et al ldquoIdentification andcharacterization of a non-retinoid ligand for retinol-bindingprotein 4which lowers serum retinol-binding protein 4 levels invivordquo Journal of Biological Chemistry vol 284 no 12 pp 7673ndash7680 2009

[179] F C George ldquoFuel metabolism in starvationrdquo Annual review ofnutrition vol 26 pp 1ndash22 2006

[180] M C Carey D M Small and C M Bliss ldquoLipid digestion andabsorptionrdquo Annual Review of Physiology vol 45 pp 651ndash6771983

[181] K Jaworski E Sarkadi-Nagy R E Duncan M Ahmadian andH S Sul ldquoRegulation of triglyceride metabolism IV Hormonalregulation of lipolysis in adipose tissuerdquo The American Journalof Physiology vol 293 no 1 pp G1ndashG4 2007

[182] R J Havel ldquoPostprandial lipid metabolism an overviewrdquoProceedings of the Nutrition Society vol 56 no 2 pp 659ndash6661997

[183] E F Brown andA FMorgan ldquoThe effect of vitamin a deficiencyupon the nitrogenmetabolism of the rat two figuresrdquo Journal ofNutrition vol 35 no 4 pp 425ndash438 1948

[184] R Zolfaghari andAC Ross ldquoEffect of vitaminAdeficiency andretinoic acid repletion on intestinal and hepatic apolipoproteinA-ImRNA levels of adult ratsrdquo Journal of Lipid Research vol 35no 11 pp 1985ndash1992 1994

[185] A Nagasaki T Kikuchi K Kurata S Masushige T Hasegawaand S Kato ldquoVitamin A regulates the expression of apolipopro-tein AI and CIII genes in the ratrdquo Biochemical and BiophysicalResearch Communications vol 205 no 3 pp 1510ndash1517 1994

[186] J Ribalta J Girona J C Vallve A E la Ville M Heras and LMasana ldquoVitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemiardquo Journalof Lipid Research vol 40 no 3 pp 426ndash431 1999

[187] L B Oliveros M A Domeniconi V A Vega L V Gatica AM Brigada andM S Gimenez ldquoVitaminA deficiencymodifieslipidmetabolism in rat liverrdquoBritish Journal of Nutrition vol 97no 2 pp 263ndash272 2007

[188] L M Zucker and T F Zucker ldquoFatty a newmutation in the ratrdquoJournal of Heredity vol 52 no 6 pp 275ndash278 1961

[189] M Iida T Murakami K Ishida A Mizuno M Kuwajima andK Shima ldquoSubstitution at codon 269 (glutamine rarr proline) ofthe leptin receptor (OB-R) cDNA is the only mutation foundin the Zucker fatty (fafa) ratrdquo Biochemical and BiophysicalResearch Communications vol 224 no 2 pp 597ndash604 1996

[190] M S Phillips Q Liu H A Hammond et al ldquoLeptin receptormissense mutation in the fatty Zucker ratrdquoNature Genetics vol13 no 1 pp 18ndash19 1996

[191] K Takaya Y Ogawa N Isse et al ldquoMolecular cloning of ratleptin receptor isoform complementary DNAs-identification ofa missense mutation in Zucker fatty (fafa) ratsrdquo Biochemicaland Biophysical Research Communications vol 225 no 1 pp75ndash83 1996

[192] A Aleixandre de Artinano andMMiguel Castro ldquoExperimen-tal rat models to study the metabolic syndromerdquo British Journalof Nutrition vol 102 no 9 pp 1246ndash1253 2009

[193] R H Unger ldquoHow obesity causes diabetes in Zucker diabeticfatty ratsrdquo Trends in Endocrinology and Metabolism vol 8 no7 pp 276ndash282 1997

[194] B S Chertow W S Blaner and N G Baranetsky ldquoEffectsof vitamin A deficiency and repletion on rat insulin secretionin vivo and in vitro from isolated isletsrdquo Journal of ClinicalInvestigation vol 79 no 1 pp 163ndash169 1987

[195] H A Koistinen A Remitz H Gylling T A Miettinen VA Koivisto and P Ebeling ldquoDyslipidemia and a reversibledecrease in insulin sensitivity induced by therapy with 13-cis-retinoic acidrdquo DiabetesMetabolism Research and Reviews vol17 no 5 pp 391ndash395 2001

[196] F Lyons M F Laker and J R Marsden ldquoEffect of oral 13-cis-retinoic acid on serum lipidsrdquo British Journal of Dermatologyvol 107 no 5 pp 591ndash595 1982

[197] J R Marsden T R Trinick M F Laker and S Shuster ldquoEffectsof isotretinoin on serum lipids and lipoproteins liver andthyroid functionrdquo Clinica Chimica Acta vol 143 no 3 pp 243ndash251 1984

[198] A S Vieira V Beijamini and A C Melchiors ldquoThe effect ofisotretinoin on triglycerides and liver aminotransferasesrdquoAnaisBrasileiros de Dermatologia vol 87 pp 382ndash387 2012

[199] V A Miller J R Rigas J R F Muindi et al ldquoModulation ofall-trans retinoic acid pharmacokinetics by liarozolerdquo CancerChemotherapy and Pharmacology vol 34 no 6 pp 522ndash5261994

[200] M S Tallman and H C Kwaan ldquoReassessing the hemostaticdisorder associated with acute promyelocytic leukemiardquo Bloodvol 79 no 3 pp 543ndash553 1992

[201] L E Gerber and J W Erdman Jr ldquoRetinoic acid and hyper-triglyceridemiardquo Annals of the New York Academy of Sciencesvol 359 pp 391ndash392 1981

[202] L E Gerber and J W Erdman Jr ldquoEffect of retinoic acid andretinyl acetate feeding upon lipid metabolism in adrenalec-tomized ratsrdquo Journal of Nutrition vol 109 no 4 pp 580ndash5891979

[203] L E Gerber and J W Erdman Jr ldquoComparative effects of all-trans and 13-cis retinoic acid administration on serum and liverlipids in ratsrdquo Journal of Nutrition vol 110 no 2 pp 343ndash3511980

[204] N S Shachter ldquoApolipoproteins C-I and C-III as importantmodulators of lipoprotein metabolismrdquo Current Opinion inLipidology vol 12 no 3 pp 297ndash304 2001

[205] N Maeda H Li D Lee P Oliver S H Quarfordt andJ Osada ldquoTargeted disruption of the apolipoprotein C-IIIgene in mice results in hypotriglyceridemia and protectionfrom postprandial hypertriglyceridemiardquo Journal of BiologicalChemistry vol 269 no 38 pp 23610ndash23616 1994

[206] Y Ito N Azrolan A OrsquoConnell A Walsh and J L BreslowldquoHypertriglyceridemia as a result of human Apo CIII geneexpression in transgenic micerdquo Science vol 249 no 4970 pp790ndash793 1990

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

20 ISRN Hepatology

[207] N Vu-Dac P Gervois I P Torra et al ldquoRetinoids increasehuman apo C-III expression at the transcriptional level via theretinoid X receptor contribution to the hypertriglyceridemicaction of retinoidsrdquo Journal of Clinical Investigation vol 102 no3 pp 625ndash632 1998

[208] P J A Davies S A Berry G L Shipley et al ldquoMetaboliceffects of rexinoids tissue-specific regulation of lipoproteinlipase activityrdquoMolecular Pharmacology vol 59 no 2 pp 170ndash176 2001

[209] J A A Ladias M Hadzopoulou-Cladaras D Kardassis et alldquoTranscriptional regulation of human apolipoprotein genesapoB apoCIII and apoAII by members of the steroid hormonereceptor superfamily HNF-4 ARP- 1 EAR-2 and EAR-3rdquoJournal of Biological Chemistry vol 267 no 22 pp 15849ndash158601992

[210] M Chen J L Breslow W Li and T Leff ldquoTranscriptionalregulation of the apoC-III gene by insulin in diabetic micecorrelation with changes in plasma triglyceride levelsrdquo Journalof Lipid Research vol 35 no 11 pp 1918ndash1924 1994

[211] RMukherjee P J A Davies D L Crombie et al ldquoSensitizationof diabetic and obese mice to insulin by retinoid X receptoragonistsrdquo Nature vol 386 no 6623 pp 407ndash410 1997

[212] M L Bonet J Ribot and A Palou ldquoLipid metabolism inmammalian tissues and its control by retinoic acidrdquo Biochimicaet Biophysica Acta vol 1821 no 1 pp 177ndash189 2012

[213] D-C Manolescu A Sima and P V Bhat ldquoAll-trans retinoicacid lowers serum retinol-binding protein 4 concentrationsand increases insulin sensitivity in diabetic micerdquo Journal ofNutrition vol 140 no 2 pp 311ndash316 2010

[214] R Yasmeen S M Jeyakumar B Reichert F Yang and OZiouzenkova ldquoThe contribution of vitamin A to autocrineregulation of fat depotsrdquoBiochimica et Biophysica Acta vol 1821no 1 pp 190ndash197 2012

[215] I Shimomura M Matsuda R E Hammer Y Bashmakov MS Brown and J L Goldstein ldquoDecreased IRS-2 and increasedSREBP-1c lead to mixed insulin resistance and sensitivity inlivers of lipodystrophic and obob micerdquoMolecular Cell vol 6no 1 pp 77ndash86 2000

[216] S S Chernick and I L Chaikoff ldquoInsulin and hepatic utilizationof glucose for lipogenesisrdquo The Journal of Biological Chemistryvol 186 no 2 pp 535ndash542 1950

[217] D W Allmann D D Hubbard and D M Gibson ldquoFatty acidsynthesis during fat-free refeeding of starved ratsrdquo Journal ofLipid Research vol 6 pp 63ndash74 1965

[218] D N Burton J M Collins A L Kennan and J W PorterldquoThe effects of nutritional and hormonal factors on the fatty acidsynthetase level of rat liverrdquo Journal of Biological Chemistry vol244 no 16 pp 4510ndash4516 1969

[219] M R Lakshmanan C M Nepokroeff and J W PorterldquoControl of the synthesis of fatty-acid synthetase in rat liver byinsulin glucagon and adenosine 3101584051015840 cyclic monophosphaterdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 69 no 12 pp 3516ndash3519 1972

[220] J D Paulauskis and H S Sul ldquoHormonal regulation of mousefatty acid synthase gene transcription in liverrdquo Journal ofBiological Chemistry vol 264 no 1 pp 574ndash577 1989

[221] J W Porter and T L Swenson ldquoInduction of fatty acidsynthetase and acetyl-CoA carboxylase by isolated rat livercellsrdquo Molecular and Cellular Biochemistry vol 53-54 no 1-2pp 307ndash325 1983

[222] J D Horton ldquoPhysiology unfolding lipid metabolismrdquo Sciencevol 320 no 5882 pp 1433ndash1434 2008

[223] G Liang J Yang J D Horton R E Hammer J L Gold-stein and M S Brown ldquoDiminished hepatic response to fast-ingrefeeding and liver X receptor agonists in mice with selec-tive deficiency of sterol regulatory element-binding protein-1crdquoJournal of Biological Chemistry vol 277 no 11 pp 9520ndash95282002

[224] I Shimomura Y Bashmakov S Ikemoto J D Horton MS Brown and J L Goldstein ldquoInsulin selectively increasesSREBP-1C mRNA in the livers of rats with streptozotocin-induced diabetesrdquo Proceedings of the National Academy ofSciences of the United States of America vol 96 no 24 pp13656ndash13661 1999

[225] G Chen G Liang J Ou J L Goldstein andM S Brown ldquoCen-tral role for liver X receptor in insulin-mediated activation ofSREBP-1c transcription and stimulation of fatty acid synthesisin liverrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 101 no 31 pp 11245ndash11250 2004

[226] J Haas J Miao D Chanda et al et al ldquoHepatic insulin sig-naling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expressionrdquo CellMetabolism vol 15 no 6 pp 873ndash884 2012

[227] R Li W Chen Y Li Y Zhang and G Chen ldquoRetinoidssynergized with insulin to induce Srebp-1c expression andactivated its promoter via the two liver X receptor bindingsites that mediate insulin actionrdquo Biochemical and BiophysicalResearch Communications vol 406 no 2 pp 268ndash272 2011

[228] Y Shirakami S-A Lee R D Clugston and W S BlanerldquoHepatic metabolism of retinoids and disease associationsrdquoBiochimica et Biophysica Acta vol 1821 no 1 pp 124ndash136 2012

[229] S Zhao R Li Y Li W Chen Y Zhang and G Chen ldquoRolesof vitamin A status and retinoids in glucose and fatty acidmetabolismrdquo Biochemistry and Cell Biology vol 90 pp 1ndash112012

[230] X Fan AMolotkov S-I Manabe et al ldquoTargeted disruption ofAldh1a1 (Raldh1) provides evidence for a complex mechanismof retinoic acid synthesis in the developing retinardquo Molecularand Cellular Biology vol 23 no 13 pp 4637ndash4648 2003

[231] F W Kiefer G Orasanu S Nallamshetty et al ldquoRetinaldehydedehydrogenase 1 coordinates hepatic gluconeogenesis and lipidmetabolismrdquo Endocrinology vol 153 no 7 pp 3089ndash3099 2012

[232] M D M Huq N-P Tsai P Gupta and L-N Wei ldquoRegulationof retinal dehydrogenases and retinoic acid synthesis by choles-terol metabolitesrdquo EMBO Journal vol 25 no 13 pp 3203ndash32132006

[233] J M Starkey Y Zhao R G Sadygov et al ldquoAltered retinoic acidmetabolism in diabetic mouse kidney identified by 18O isotopiclabeling and 2D mass spectrometryrdquo PLoS ONE vol 5 no 6Article ID e11095 2010

[234] J M Friedman ldquoLeptin at 14 y of age an ongoing storyrdquo TheAmerican Journal of Clinical Nutrition vol 89 no 3 pp 973ndash979 2009

[235] M J Adams T L Blundell E J Dodson et al ldquoStructure ofrhombohedral 2 zinc insulin crystalsrdquoNature vol 224 no 5218pp 491ndash495 1969

[236] P De Meyts ldquoInsulin and its receptor structure function andevolutionrdquo BioEssays vol 26 no 12 pp 1351ndash1362 2004

[237] M Kasuga F A Karlsson and C R Kahn ldquoInsulin stimulatesthe phosphorylation of the 95000-dalton subunit of its ownreceptorrdquo Science vol 215 no 4529 pp 185ndash187 1982

[238] LM Petruzzelli S Ganguly andC J Smith ldquoInsulin activates atyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Hepatology 21

and human placentardquo Proceedings of the National Academy ofSciences of the United States of America vol 79 no 22 I pp6792ndash6796 1982

[239] N M McKern M C Lawrence V A Streltsov et al ldquoStructureof the insulin receptor ectodomain reveals a folded-over con-formationrdquo Nature vol 443 no 7108 pp 218ndash221 2006

[240] P Cohen ldquoThe twentieth century struggle to decipher insulinsignallingrdquo Nature Reviews Molecular Cell Biology vol 7 no 11pp 867ndash873 2006

[241] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[242] M F White ldquoIRS proteins and the common path to diabetesrdquoThe American Journal of Physiology vol 283 no 3 pp E413ndashE422 2002

[243] J Avruch ldquoMAP kinase pathways the first twenty yearsrdquoBiochimica et Biophysica Acta vol 1773 no 8 pp 1150ndash11602007

[244] B DManning and L C Cantley ldquoAKTPKB Signaling navigat-ing Downstreamrdquo Cell vol 129 no 7 pp 1261ndash1274 2007

[245] J K Osborne E Zaganjor and M H Cobb ldquoSignal controlthrough Raf in sickness and in healthrdquo Cell Research vol 22no 1 pp 14ndash22 2012

[246] K D Copps and M F White ldquoRegulation of insulin sensitivityby serinethreonine phosphorylation of insulin receptor sub-strate proteins IRS1 and IRS2rdquo Diabetologia vol 55 no 10 pp2565ndash2582 2012

[247] K Norris F Norris D H Kono et al ldquoExpression of protein-tyrosine phosphatases in the major insulin target tissuesrdquo FEBSLetters vol 415 no 3 pp 243ndash248 1997

[248] L Agius andM Peak ldquoInteractions of okadaic acid with insulinaction in hepatocytes role of protein phosphatases in insulinactionrdquo Biochimica et Biophysica Acta vol 1095 no 3 pp 243ndash248 1991

[249] K Siddle ldquoSignalling by insulin and IGF receptors supportingacts and new playersrdquo Journal of Molecular Endocrinology vol47 no 1 pp R1ndashR10 2011

[250] DW Haslam andW P T James ldquoObesityrdquoTheLancet vol 366no 9492 pp 1197ndash1209 2005

[251] B M Popkin and P Gordon-Larsen ldquoThe nutrition transitionworldwide obesity dynamics and their determinantsrdquo Interna-tional Journal of Obesity vol 28 no 3 pp S2ndashS9 2004

[252] J C KWells ldquoThrift a guide to thrifty genes thrifty phenotypesand thrifty normsrdquo International Journal of Obesity vol 33 no12 pp 1331ndash1338 2009

[253] J S Sweeney ldquoDietary factors that influence the dextrose tol-erance test a preliminary studyrdquo Archives of Internal Medicinevol 40 no 6 pp 818ndash830 1927

[254] P A Hansen D H Han B A Marshall et al ldquoA highfat diet impairs stimulation of glucose transport in musclefunctional evaluation of potential mechanismsrdquo Journal ofBiological Chemistry vol 273 no 40 pp 26157ndash26163 1998

[255] J D McGarry ldquoGlucose-fatty acid interactions in health anddiseaserdquoThe American Journal of Clinical Nutrition vol 67 no3 pp 500Sndash504S 1998

[256] M G Myers R L Leibel R J Seeley and M W SchwartzldquoObesity and leptin resistance distinguishing cause fromeffectrdquoTrends in Endocrinology andMetabolism vol 21 no 11 pp 643ndash651 2010

[257] Y H Yu and H N Ginsberg ldquoAdipocyte signaling and lipidhomeostasisrdquo Circulation Research vol 96 no 10 pp 1042ndash1052 2005

[258] J Denis McGarry ldquoDysregulation of fatty acid metabolism inthe etiology of type 2 diabetesrdquo Diabetes vol 51 no 1 pp 7ndash182002

[259] B M Spiegelman and J S Flier ldquoObesity and the regulation ofenergy balancerdquo Cell vol 104 no 4 pp 531ndash543 2001

[260] J D Horton J L Goldstein and M S Brown ldquoSREBPsactivators of the complete program of cholesterol and fatty acidsynthesis in the liverrdquo Journal of Clinical Investigation vol 109no 9 pp 1125ndash1131 2002

[261] M S Brown and J L Goldstein ldquoSelective versus total insulinresistance a pathogenic paradoxrdquo Cell Metabolism vol 7 no 2pp 95ndash96 2008

[262] Y-A Moon G Liang X Xie et al ldquoThe ScapSREBP pathwayis essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animalsrdquo Cell Metabolism vol15 no 2 pp 240ndash246 2012

[263] J L Owen Y Zhang S H Bae et al ldquoInsulin stimulation ofSREBP-1c processing in transgenic rat hepatocytes requires p70S6-kinaserdquo Proceedings of the National Academy of Sciences vol109 no 40 pp 16184ndash16189 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom