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doi:10.1152/ajpendo.90899.2008296:E1183-E1194, 2009. First published 21 January 2009;Am J Physiol Endocrinol Metab

Jahangir Iqbal and M. Mahmood HussainIntestinal lipid absorption

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Review

Intestinal lipid absorption

Jahangir Iqbal and M. Mahmood Hussain

Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York

Submitted 7 November 2008; accepted in final form 19 January 2009

Iqbal J, Hussain MM. Intestinal lipid absorption. Am J Physiol Endo-crinol Metab 296: E1183E1194, 2009. First published January 21, 2009;doi:10.1152/ajpendo.90899.2008.Our knowledge of the uptake and transportof dietary fat and fat-soluble vitamins has advanced considerably. Researchers haveidentified several new mechanisms by which lipids are taken up by enterocytes andpackaged as chylomicrons for export into the lymphatic system or clarified theactions of mechanisms previously known to participate in these processes. Fattyacids are taken up by enterocytes involving protein-mediated as well as protein-independent processes. Net cholesterol uptake depends on the competing activitiesof NPC1L1, ABCG5, and ABCG8 present in the apical membrane. We have consid-erably more detailed information about the uptake of products of lipid hydrolysis, theactive transport systems by which they reach the endoplasmic reticulum, the mecha-nisms by which they are resynthesized into neutral lipids and utilized within theendoplasmic reticulum to form lipoproteins, and the mechanisms by which lipoproteins

are secreted from the basolateral side of the enterocyte. apoB and MTP are known tobe central to the efficient assembly and secretion of lipoproteins. In recent studies,investigators found that cholesterol, phospholipids, and vitamin E can also be secretedfrom enterocytes as components of high-density apoB-free/apoAI-containing lipopro-teins. Several of these advances will probably be investigated further for their potentialas targets for the development of drugs that can suppress cholesterol absorption, therebyreducing the risk of hypercholesterolemia and cardiovascular disease.

intestine; dietary fat; triacylglycerol; cholesterol; phospholipids; fat-soluble vita-mins; microsomal triglyceride transfer protein

DIETARY FATS CONSIST OF A WIDE ARRAY of polar and nonpolarlipids (32, 33). Triacylglycerol (TAG) is the dominant fat in thediet, contributing 9095% of the total energy derived from

dietary fat. Dietary fats also include phospholipids (PLs),sterols (e.g., cholesterol), and many other lipids (e.g., fat-soluble vitamins). The predominant PL in the intestinal lumenis phosphatidylcholine (PC), which is derived mostly from bile(1020 g/day in humans) but also from the diet (12 g/day).The predominant dietary sterols are cholesterol (mostly ofanimal origin) and -sitosterol (the major plant sterol). Al-though -sitosterol accounts for 25% of dietary sterols, it is notabsorbed by humans under physiological conditions.

Researchers have been investigating the various steps in-volved in lipid digestion, absorption, and metabolism to iden-tify factors that could serve as targets for the development ofdrugs capable of reducing the risk of lipid-associated disorders,

including dyslipidemias and cardiovascular disease. In so do-ing, they have explored key aspects of lipid digestion hydro-lysis, emulsification, and micelle formation. They have alsoexplored key issues of absorption, e.g., the uptake of theproducts of lipid hydrolysis by enterocytes (the epithelial cellslining the walls of the intestinal lumen) and their transport tointracellular compartments, where fatty acids and sterols aretransformed into neutral lipids. Efficient absorption ensures

that dietary fat is available to be used as a source of energy thatsupports various cellular functions or to be stored and serve asreservoirs for lipoprotein trafficking, bile acid synthesis, ste-

roidogenesis, membrane formation and maintenance, and epi-dermal integrity in various mammalian cells. Excess fat isstored in cytosolic lipid droplets until it is needed to supportintracellular processes.

In this review, we will concentrate on the biochemicalprocesses involved in the digestion and absorption of the mostcommon dietary lipids: TAGs, PLs, cholesterol, and fat-solublevitamins.

DIGESTION AND ABSORPTION OF LIPIDS:

A BRIEF OVERVIEW

The digestion of lipids begins in the oral cavity through

exposure to lingual lipases, which are secreted by glands in thetongue to begin the process of digesting triglycerides. Diges-tion continues in the stomach through the effects of bothlingual and gastric enzymes. The stomach is also the major sitefor the emulsification of dietary fat and fat-soluble vitamins,with peristalsis a major contributing factor. Crude emulsions oflipids enter the duodenum as fine lipid droplets and then mixwith bile and pancreatic juice to undergo marked changes inchemical and physical form. Emulsification continues in theduodenum along with hydrolysis and micellization in prepara-tion for absorption across the intestinal wall. (For details aboutthe emulsification, hydrolysis, and micellization of fats, seeRefs. 131 and 144.)

Address for reprint requests and other correspondence: J. Iqbal or M. M.Hussain, Dept. of Anatomy and Cell Biology, 450 Clarkson Ave., StateUniversity of New York Downstate Medical Center, Brooklyn, NY 11203(e-mail: [email protected] or [email protected]).

Am J Physiol Endocrinol Metab 296: E1183E1194, 2009.First published January 21, 2009; doi:10.1152/ajpendo.90899.2008.

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Bile and pancreatic juice provide pancreatic lipase, bile salts,and colipase, which function cooperatively to ensure the effi-ciency of lipid digestion and absorption. The importance ofbile to the efficiency of these processes is indicated by thedecreased rate of lipid absorption in humans with bile fistulas.The greatly reduced concentration of bile acid in the duodenumof such individuals suggests that bile salts, although possibly

not absolutely necessary for digestion, are essential for thecomplete absorption of dietary fats (150). Elevated concentra-tions of bile salts have been shown to inhibit pancreatic lipaseactivity in the duodenum (190). Such inhibition is offset,however, by colipase, which has been shown in vitro to restorepancreatic lipase activity under such circumstances (112, 128).The importance of colipase in the digestion of fat was indicatedin a clinical report of steatorrhea in two brothers with acongenital absence of colipase, which indicated that the ste-atorrhea decreased with the administration of colipase (76). Ithas also been demonstrated in colipase-deficient mice (41),which, when placed on a high-fat diet, developed steatorrheathat was so severe that undigested lipids could be seen in theirfeces. When these mice were placed on a low-fat diet, theirability to digest fat returned to normal. These findings suggestthat colipase plays a critical, but not essential, role in thedigestion of dietary lipids by pancreatic lipases.

Triacylglycerides

Digestion and absorption of TAGs. TAG is digested primar-ily by pancreatic lipase in the upper segment of the jejunum.This process generates a liquid-crystalline interface at thesurface of the emulsion particles (13, 161). The activity ofpancreatic lipase on the sn-1 and sn-3 positions of the TAGmolecule results in the release of 2-monoacylglycerol (2-MAG) and free fatty acids (FFAs) (122124); 2-MAG is the

predominant form in which MAG is absorbed from the smallintestine. The formation of 2-MAG (and 1-MAG) throughisomerization in an aqueous medium occurs more slowly thanthe uptake of 2-MAG from the small intestine (20). Furtherhydrolysis of 1- or 2-MAG by pancreatic lipase results in theformation of glycerol and FFAs (78); cholesterol esterase canalso hydrolyze the acyl group at the sn-2 position to formglycerol and FFAs (111).

Free fatty acids are taken up from the intestinal lumen intothe enterocytes and used for the biosynthesis of neutral fats. Aprotein-independent diffusion model and protein-dependentmechanisms have been proposed for the uptake and transportof fatty acids (FAs) across the apical membrane of the entero-cyte (for details, see Ref. 119). A number of candidate proteins

have been proposed to take part in protein-dependent uptakemechanisms. FAT/CD36 plays a key role in the uptake of FAs(1, 19). FAT/CD36 is highly expressed in the intestine (37),and its expression is upregulated by the presence of dietary fat(148), genetic obesity, and diabetes mellitus (64). Studies inCD36-null mice suggest that it is intimately involved in theuptake and transport of FAs targeted for transport to thelymphatic system through their use in the assembly of chylo-microns (45). This relationship is suggested by the finding thatthe uptake of FAs is not impaired in CD36-null animals.However, lipids tend to accumulate in the proximal smallintestine of these animals primarily because of decreasedtransport of FAs to the lymphatic system (45). FA transport

proteins (FATPs) are well represented in the small intestine bytheir FATP4 isoform, which is thought to help facilitate theuptake of FAs by the enterocytes (162).

TAG synthesis. Once inside the enterocyte, the products ofTAG hydrolysis must traverse the cytoplasm to reach theendoplasmic reticulum (ER), where they are used to synthesizecomplex lipids. Specific binding proteins carry FAs and MAG

to the intracellular site, where they will be used for TAGbiosynthesis. The two major fatty acid-binding proteins(FABPs) found in enterocytes are liver FABP and intestinalFABP (2, 16, 69). Most TAG biosynthesis in the enterocyteoccurs along the MAG pathway, in which MAG and fattyacyl-CoA are covalently joined to form diacylglycerol (DAG)in a reaction catalyzed by monoacylglycerol acyltransferases(MGATs) (40, 197). Further acylation of DAG by diacylglycerolacyltransferase (DGAT) leads to the synthesis of TAG. TwoDGATs have been identified and characterized: DGAT1 andDGAT2. [For additional information about DGATs, refer tothe recent review (197).] DGAT2 is expressed mainly in theliver and intestine. Its importance in the absorption of fat hasbeen demonstrated by a reduction in fat absorption in DGAT2-knockout (KO) animals. DGAT1, which is expressed in severaltissues (including liver, intestine, and skin), differs fromDGAT2 in that defective fat absorption is not seen inDGAT1-KO mice. In recent studies, investigators have foundthat MGAT2 (29, 31) and MGAT3 (30) possess DGAT activity(26, 170). Some TAG synthesis also occurs through the de-phosphorylation of phosphatidic acid and acylation of theresultant DAG. Thus, several enzymes take part in the biosyn-thesis of TAG in intestinal cells.

Use of TAG in lipoprotein assembly. The existence ofmultiple pools of DAG (159, 160) and TAG (51, 55, 60, 104,175, 183, 195) has been known for some time. Using differ-entiated human colon carcinoma (Caco-2) cells, Luchoomun

and Hussain (115) showed that nascent TAG is used preferen-tially for chylomicron assembly. TAG is also synthesized denovo from fatty acyl chains and glycerol phosphate. Whengenerated through this pathway, however, TAG is only partlyused to assemble nascent apolipoprotein (apo)B-containinglipoproteins. Most of the TAG synthesized through this path-way enters the cytosolic pool to be used to generate a distinctpool of DAG. (For a review of this topic, see Ref. 202.) DAGesterification also occurs in the ER lumen (142), where theresultant TAG binds to the microsomal triglyceride transportprotein (MTP), which participates in the assembly and secre-tion of neutral lipids in chylomicrons. This process is describedfurther in a subsequent section in this review. (For additionalinformation, also see Refs. 18 and 119.)

Phospholipids

The predominant PL in the lumen of the small intestine isPC, which is found in mixed micelles that also contain cho-lesterol and bile salts. The digestion of PLs is carried outprimarily by pancreatic phospholipase A2 (pPLA2) and otherlipases secreted by the pancreas in response to food intake.These lipases interact with PLs at the sn-2 position to yieldFFAs and lysophosphatidylcholine (21, 182). These productsof lipolysis are removed from the water-oil interface when theyare incorporated into the mixed micelles that form spontane-ously when they interact with bile salts. Having both hydro-

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philic and hydrophobic components, bile salts are able tofacilitate micelle formation; MAG and PL enhance their abilityto form mixed micelles. pPLA2-KO mice are indistinguishablefrom wild-type controls when fed regular chow, except fortheir resistance to diet-induced obesity (84). Increased excre-tion of TAG, on a high-fat diet, in the feces of pPLA2-KO miceindicates that pPLA2 deficiency has a greater effect on the

digestion of TAG than that of PL hydrolysis (84). It does notaffect PL hydrolysis and absorption, possibly because its ac-tivity is compensated for by other PLA2 enzymes (158).

Cholesterol

Cholesterol in the body represents both endogenoussources (produced in the liver and peripheral tissues) anddietary sources absorbed from the intestine (186). Thehuman diet provides 400 mg of cholesterol daily, and theliver secretes 1 g daily (66, 194). Approximately 50% ofthe cholesterol in the intestine is absorbed; the remainder isexcreted in feces (10, 39).

Digestion. Only nonesterified cholesterol can be incorpo-

rated into bile acid micelles and absorbed by enterocytes. Mostdietary cholesterol exists in the form of the free sterol, withonly 1015% existing as the cholesteryl ester. The latter mustbe hydrolyzed by cholesterol esterase to release free choles-terol for absorption. Cholesterol is only minimally soluble inan aqueous environment (82, 177) and thus must be partitionedinto bile salt micelles prior to absorption. It usually enters thesemicelles along with TAGs and PLs, ionized and nonionizedFAs, MAGs, and lysophospholipids to form mixed micelles(74, 196). These micelles are transported to the brush border ofthe enterocyte, where cholesterol is absorbed. Its absorptiondepends on the presence of bile acids in the intestinal lumen(191) and correlates directly with the total bile acid pool (149).

Absorption: cholesterol uptake. Cholesterol must passthrough a diffusion barrier at the intestinal lumen-enterocytemembrane interface before it can interact with transporterproteins responsible for its uptake and subsequent transportacross the cellular brush border. Bile salt micelles facilitate thetransfer of cholesterol across the unstirred water layer. Themechanism by which the cholesterol in micelles is taken up bythe cell and crosses the brush-border membrane is still underinvestigation. Cholesterol absorption had long been consideredan energy-independent, simple, passive diffusion process.However, it is taken up by the enterocyte with relatively highefficiency compared with structurally similar phytosterols(130). New evidence strongly suggests that a transporter-facilitated mechanism is involved. Interindividual differences

and interstrain variations in the efficiency of intestinal choles-terol absorption (195, 196) support this suggestion, as does thediscovery that multiple genes (4, 14, 106, 113) participate inthe regulation of cholesterol absorption and several moleculesappear to inhibit it (59).

Absorption: cholesterol transport. Several proteins havebeen investigated for their potential roles as intestinal choles-terol transporters, but evidence for their direct role in theuptake of cholesterol remains elusive. Studies in geneticallymodified animal models have helped investigators gain impor-tant insights into the mechanisms of transport and identity oftransporter proteins. Through these studies, investigators haveidentified Niemann-Pick C1 like 1 (NPC1L1) as a cholesterol

uptake transporter (4) and the ATP-binding cassette (ABC)proteins ABCG5 and ABCG8 as cholesterol efflux transporters(14, 106, 113). These three molecules appear to be key playersin the control of the cholesterol absorption from the intestinallumen.

ABCG5 and ABCG8, which function as a heterodimer (62),are critical for the control of sterol absorption. Mutations in the

genes encoding human ABCG5 and ABCG8 transporters cause-sitosterolemia (14, 106, 113), which is characterized by theaccumulation of plant sterols in blood and other tissues as aresult of their enhanced absorption from the intestines anddecreased removal in bile. These proteins are localized at thecanalicular membrane of hepatocytes and at the brush border ofenterocytes. Abcg5/g8 deficiency in mice results in reducedbiliary cholesterol secretion (199) and enhanced phytosterolabsorption (102, 146, 199) but has only minimal effects on theefficiency of cholesterol absorption (146, 199). The pharma-cological induction or overexpression of Abcg5 and Abcg8 inmice (199 201) results in a reduction in fractional cholesterolabsorption (i.e., the percentage of cholesterol absorbed fromthe intestine, which is determined using a dual-isotope feedingtechnique) and indicates that ABCG5 and ABCG8 play a rolein the control of cholesterol absorption under certainconditions.

The identification of NPC1L1 as a putative cholesteroltransporter in the enterocytes (4) was facilitated by the discov-ery of the cholesterol absorption inhibitor ezetimibe (4, 59),which reduces diet-induced hypercholesterolemia (49, 56, 103,187, 203). NPC1L1 is a glycosylated protein localized at thebrush-border membrane of the enterocyte (95). The deletion ofNpc1l1 in mice results in a reduction in fractional cholesterolabsorption (4). Ezetimibe has been shown to bind to NPC1L1-expressing cells and to the intestinal brush border (59). Dele-tion of Npc1l1 also results in the elimination of the binding

capacity of the brush border (59), which indicates that NPC1L1is a target of ezetimibe.A sterol regulatory element in the promoter and a sterol-

sensing domain of NPC1L1 appear to regulate cholesterolabsorption in response to cholesterol intake. Expression ofNpc1l1 is enhanced in the cholesterol-depleted porcine intes-tine and suppressed in mice placed on a cholesterol-rich diet(83). Most of the NPC1L1 in the body is found in intracellularmembranes. However, cholesterol deprivation induces itstranslocation to the plasma membrane, where it can pick upcholesterol and transport it to the ER for esterification andpackaging into nascent lipoproteins (50, 198).

Reducing the expression of NPC1L1 at the level of tran-scription may reduce cholesterol absorption. Activation of the

nuclear receptor peroxisome proliferator-activated receptor(PPAR)/ by the synthetic agonist GW610742 has beenshown to reduce cholesterol absorption by decreasing Npc1l1expression without altering the expression ofAbcg5 and Abcg8(185). A decrease in Npc1l1 expression has also been observedfollowing treatment of human colon-derived Caco-2 cells withligands for PPAR/ but not for PPAR or PPAR (185).

Absorption: other regulatory factors. The nuclear liver Xreceptors (LXRs) LXR (expressed mainly in the liver, kidney,intestine, spleen, and adrenals) and LXR (expressed ubiqui-tously) regulate pathways involved in the metabolism of cho-lesterol and in lipid biosynthesis. LXR target genes have beenshown to be involved in cholesterol and lipid homeostasis. (For

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a list of target genes and their regulation, see Ref. 174.) Afteractivation by natural ligands (e.g., oxysterols), the LXR formsa heterodimer with the retinoid X receptor (96, 97) and bindsto specific LXR response elements in the promoter regions oftheir target genes to activate gene transcription. LXR targetgenes include those that express proteins involved in the effluxof cholesterol from the cell (155, 157, 174, 189) as well as bile

acid synthesis (174) and lipogenesis (174). Thus, global LXRactivation by synthetic agonists has a plethora of effects,including elevated high-density lipoprotein (HDL) levels (25,28, 98, 126, 147, 163, 178), hypertriglyceridemia (156, 163),hepatic steatosis (65), increased excretion of cholesterol in bile(147, 201), reduced efficiency of cholesterol absorption fromthe intestine (103, 157, 159, 191, 206), and increased loss ofneutral sterols in feces (201).

Other transporters, such as scavenger receptor class B type I(SR-BI), which is localized both at the apical and basolateralmembranes of enterocytes (27), have also been suspected ofhaving a role in the control of cholesterol absorption. Thepossibility that SR-BI is a cholesterol transporter is suggestedby the observation that intestine-specific overexpression ofSR-BI in mice leads to an increase in cholesterol and TAGabsorption in short-term absorption experiments (17). Theimportance of the FA translocase CD36 (which is also ex-pressed in epithelial cells lining the small intestine) in FAabsorption is well established. CD36 has also been implicatedas the cholesterol transporter in brush-border membranes. Ad-ditionally, overexpression of CD36 in COS-7 cells has beenshown to enhance cholesterol uptake from micellar substrates(184). In another study, CD36-null mice showed a significantreduction in cholesterol transport from the intestinal lumen tothe lymphatic system (133). Decreased cholesterol uptake hasbeen shown in brush-border membrane vesicles prepared fromthe proximal (but not distal) intestine of SR-BI-KO mice (184)

and in brush-border membrane vesicles and Caco-2 cells pre-incubated with antibodies to SR-BI (71). However, targeteddisruption ofSR-BIin mice has little effect on in vivo intestinalcholesterol absorption (3, 120, 192), which suggests that SR-BImight not be essential for absorption of cholesterol from theintestine.

Another potential step in the regulation of cholesterol ab-sorption involves two ER membrane-localized enzymes, acyl-CoA:cholesterol acyltransferase 1 (ACAT1) and ACAT2, thatcatalyze the esterification of intracellular cholesterol (107).ACAT1 is expressed in many tissues (36, 61), but its level ofexpression in the mouse small intestine is very low (125). Bycontrast, ACAT2 expression is restricted to the small intestineand liver (6, 35, 137). ACAT2 is highly specific for cholesterol

and does not esterify plant sterols. It is the predominantenzyme responsible for the synthesis of cholesterol esters andtheir subsequent secretion with lipoproteins. ACAT2 defi-ciency results in a considerable decrease in the rate of choles-terol absorption (26). The rate of cholesterol esterification inthe presence of these enzymes is notably enhanced by substrateavailability, but, as we demonstrated recently, it is inhibited byproduct accumulation. This inhibition is relieved by MTP (94),which transfers cholesterol esters from the ER membranes tonascent apoB-lipoproteins. The importance of MTP in choles-terol absorption has been well documented (85, 86, 89).

Approximately 70 80% of cholesterol entering the lym-phatic system is esterified, which suggests that esterification is

important for bulk entry of cholesterol into nascent chylomi-crons. Reesterification of the absorbed cholesterol within theenterocyte enhances the diffusion gradient to favor the entry ofintraluminal cholesterol into the cell and is therefore an im-portant regulator of cholesterol absorption from the intestine.Thus, inhibition of ACAT by pharmacological intervention(38, 73) or deletion of Acat2 (26) significantly reduces the rate

of cholesterol absorption.It has also been suggested that ATP-binding cassette trans-

porter A1 (ABCA1) plays a role in the control of cholesterolabsorption. ABCA1 was initially thought to be localized to theapical membrane (157); more recent studies have providedevidence suggesting that it is present in the basolateral mem-brane of chicken enterocytes (132) and human Caco-2 cells(138). Our studies in Caco-2 cells and in the apoA1-KO mousemodel showed for the first time that basolateral efflux (secre-tion) of cholesterol occurs in high-density apoB-free/apoA-I-containing lipoproteins (Fig. 1) (91, 93). The importance ofABCA1 in the biogenesis of HDL in the intestine was dem-onstrated by deleting intestinal Abca1, which resulted in a 30%decrease in plasma HDL cholesterol levels (24). Enterocytesdeficient in ABCA1 absorb smaller amounts of cholesterol(24). Thus, HDL contributes considerably to cholesterol ab-sorption from the intestine. The origin of HDL particles inmesenteric lymph fluid has been a subject of considerablecontroversy (11, 53, 117, 139, 152, 169, 188). The measure-ment of cholesterol in lymph led to the hypothesis that HDL isnot important in cholesterol transport. However, Brunhamet al. (24) recently demonstrated that the HDL in lymph isdependent on the activity of hepatic ABCA1 and enters thelymph from plasma. Thus, quantification of HDL in lymphmay not provide an accurate assessment of the extent ofcholesterol absorption via this pathway.

Vitamin E

Vitamin E is one of the most abundant lipid-soluble anti-oxidants found in the plasma and somatic cells of highermammals. Vitamin E exists in two forms, as tocopherols andtocotrienols, that vary dramatically in terms of biologicalactivity due to variations in bioavailability and in intrinsicantioxidant properties. The hydrophobic nature of vitamin Ecreates a major challenge to living organisms in maintainingadequate uptake, transport, and delivery of this vitamin tovarious tissues.

Vitamin E absorption. Micelle formation is required for theabsorption of vitamin E (57, 171). Pancreatic enzymes mayalso aid in its absorption (121); this is suggested by the finding

of vitamin E deficiency in patients with cystic fibrosis, who donot secrete pancreatic enzymes (12, 48, 70, 172, 193).

The mechanism of absorption of vitamin E from the intestineis similar to the mechanism involved in the transport of otherlipid molecules in vivo and involves molecular, biochemical,and cellular mechanisms closely related to overall lipid andlipoprotein homeostasis (22, 67, 75, 100, 101, 179181). Theuptake of vitamin E from the intestine has traditionally beenassumed to be a simple process of passive diffusion. However,in a study in Caco-2 cells, it was shown to be a rapid, saturable,temperature-dependent process (7). Recent studies suggest thatSR-BI plays a role in vitamin E absorption (154). Vitamin Eabsorption from the intestine is thought to occur predominantly

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through the secretion of chylomicrons into the lymphatic sys-tem. Consistent with this hypothesis is the observation thatvitamin E absorption is dependent on the availability of oleic

acid for triglyceride synthesis and chylomicron assembly and isinhibited by MTP inhibitors (7). The importance of alternativepathways for vitamin E absorption has also been suggested bythe observation that symptoms of vitamin E deficiency areameliorated after treatment with high doses of vitamin E inpatients deficient in chylomicrons. Indeed, intestinal vitamin Eabsorption may also occur via direct secretion from epithelialcells into the portal venous circulation by HDL efflux. ThisHDL-dependent mechanism was recently characterized inCaco-2 cells (7). Whether intestinal ABCA1 or other ABCtransporters are also critical for the absorption of vitamin Efrom the intestine and for steady-state plasma -tocopherollevels remains to be seen.

Vitamin A. The de novo synthesis of compounds withvitamin A activity is limited to plants and microorganisms.Higher animals must obtain vitamin A from the diet. The main

dietary forms of preformed vitamin A are carotenoids in fruitsand vegetables and long-chain FA esters of retinol in foods ofanimal origin (145). Carotenoids are either cleaved to generateretinol or absorbed intact, whereas retinyl esters must becompletely hydrolyzed within the intestinal lumen to releasefree retinol before retinol can be taken up by enterocytes.Hydrolysis of the retinyl esters requires lipase activity. Theproducts of TAG hydrolysis provide a better milieu for thesolubilization of vitamin E in mixed micelles.

Free retinol is taken up by intestinal mucosal cells (44). Instudies conducted in Caco-2 cells (151) and intestinal seg-ments, investigators have found that saturable carrier-mediatedprocesses at physiological concentrations (81) and nonsat-

Fig. 1. Intestinal lipid absorption. Products of lipid hydrolysis are solubilized in micelles and presented to the apical membranes of enterocytes. This membraneharbors several transport proteins that participate in the uptake of various types of lipids. Niemann-Pick C1 like 1 (NPC1L1) is a protein involved in cholesteroluptake. CD36 and fatty acid (FA) transport protein (FATP) have been shown to participate in FA transport, whereas scavenger receptor class B type I (SR-BI)is involved in vitamin E (Vit E) uptake. In the cytosol, FA-binding protein (FABP) and cellular retinol-binding protein (CRBP) transport FAs and retinol (R),respectively. Acyl-CoA:cholesterol acyltransferase (ACAT), diacylglycerol acyltransferase (DGAT), and lecithin:retinol acyltransferase (LRAT) are found in theendoplasmic reticulum (ER) membrane, where they facilitate the esterification of cholesterol, monoacylglycerols (MAG), and retinol, respectively. Theseesterified products are incorporated into apolipoprotein (apo)B48-containing chylomicrons (CM) in a microsomal triglyceride (TG) transport protein(MTP)-dependent manner. The newly synthesized prechylomicrons are transported in specialized vesicles to the Golgi apparatus for further processing and forsecretion. In addition, enterocytes express ATP-binding cassette (ABC) transporter A1 on the basolateral membrane to facilitate the efflux of cholesterol. C, freecholesterol; RE, retinyl ester; CE, cholesteryl ester; AIV, apolipoprotein A-IV.

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urable diffusion-dependent processes at pharmacological con-centrations (80) of free retinol are involved in retinol uptake.After cellular uptake, the intercellular retinol-binding proteins(CRBPs) CRBP-I and CRBP-II immediately sequester freeretinol. CRBP-I is expressed in many tissues, whereas CRBP-IIis expressed primarily in the absorptive cells of the smallintestine. CRBP-II is one of the most abundant soluble proteins

in the jejunal mucosa, which indicates that it may be uniquelysuited for the absorption of retinol from the intestine (109, 136,140, 141). In studies conducted in retinoid-deficient rats (153)and in rats placed on diets containing long-chain FAs (176),investigators found that CRBP-II mRNA expression increasedin the small intestine. In studies carried out in Caco-2 cells,investigators found that overexpression of CRBP-II or treat-ment with retinoic acid (which is associated with increasedCRBP-II mRNA expression) resulted in increased absorptionand intracellular esterification of retinol. In CRBP-II-KO mice,investigators found that CRBP-II plays an important (albeit notessential) role in the absorption of vitamin A from the intestine(47). Some of the free retinol in the enterocytes remainsassociated with CRBP, but much of the retinol is usuallyesterified by lecithin:retinol acyltransferases (LRATs) andstored within the cell (116). The recent characterization of theLRAT-KO mouse [in which no detectable tissue retinyl esterswere found (9)] has largely resolved the question of whetherenzymes such as ARAT are physiologically involved in retinolesterification in the intestine.

Metabolic studies have revealed that most of the retinylesters in plasma are present in small chylomicrons; significantamounts are found in large chylomicrons, and smaller amountsare found in very-low-density lipoproteins (VLDL) (108).Studies have been carried out in differentiated Caco-2 cellsunder postprandial conditions to determine the mechanism ofretinol secretion by the intestine. In these studies, investigators

found that a significant amount of retinyl ester was secretedmainly with chylomicrons independent of the rate of retinoluptake and intracellular levels of free or esterified retinol (134).Pluronic L81, which inhibits the secretion of chylomicrons,decreased the secretion of retinyl ester and did not result intheir increased secretion with smaller lipoproteins. This sug-gests that intestinal retinyl ester secretion is a highly specificand regulated process that is dependent on the assembly andsecretion of chylomicrons. A significant amount of retinol isalso secreted into the portal circulation, probably as freeretinol; this is expected to be physiologically significant inpathological conditions that affect the secretion of chylomi-crons (79). However, very little is known about the regulationof the retinol secretion by this pathway. Under fasting condi-

tions, Caco-2 cells secrete mainly free retinol unassociatedwith lipoproteins (134). The secretion of free retinol mayrequire facilitated transport. This notion is supported by themarked inhibition of the free retinol efflux into the basolateralmedium by glyburide, a known inhibitor of the ABCA1 trans-porter (46). Mechanisms regulating retinol output throughthese pathways are not well understood.

ASSEMBLY, SECRETION, AND REGULATION

OF INTESTINAL LIPOPROTEINS

The major lipoproteins secreted by the intestine are VLDLand chylomicrons. Of these, the chylomicrons are synthesized

exclusively in the intestine to transport dietary fat and fat-soluble vitamins into the blood (Fig. 1). Chylomicrons areprimarily very large, spherical TAG-rich particles (5, 58) thatalso contain PLs, cholesterol, vitamin E, vitamin A, and pro-tein. The lipoprotein core contains TAG, cholesteryl esters, andfat-soluble vitamins, whereas the surface contains a monolayerof PLs (mainly phosphatidylcholine), free cholesterol, and

protein (127, 204, 205). A key structural component of thechylomicron is the huge, hydrophobic, nonexchangeable pro-tein apoB48. Other proteins associated with nascent chylomi-crons (which are synthesized in enterocytes) are apoA-I, apoA-IV, and apoCs. apoB48 synthesis is generally believed to beconstitutive (88). However, the amount of lipids transportedduring the postprandial state is severalfold greater than thattransported during the fasting state. Increased transport of fatwith similar amounts of apoB48 occurs because of an increasein the size of the particles during the postprandial state (42, 43,54, 63, 72, 173). Fat feeding also increases the expression ofapoA-IV, which serves as a surface component for apoB48particles in the enterocyte (77, 135).

It has been proposed that chylomicron assembly involves thesynthesis of primordial lipoproteins followed by their coreexpansion, which results in the formation of nascent lipopro-teins (88). This basic proposal was later expanded to suggestthat chylomicron assembly may involve three independentsteps: assembly of primordial lipoproteins, formation of lipiddroplets, and core expansion (85). Subsequently, differentbiochemical signposts for various biosynthetic milestones werearticulated (89). The association of a preformed PL withnascent apoB was proposed to determine the assembly ofprimordial lipoproteins. An increase in the amount of nascentTAG would serve as an indicator of the synthesis of largerlipoproteins, and retinyl esters were proposed as markers of thecompletion of chylomicron assembly.

Chylomicron assembly occurs mainly in the ER. Theseparticles are then transported to the cis-Golgi in prechylomi-cron transport vesicles (PCTVs) (18, 105, 119). Budding of thePCTVs has been shown to require liver FABP (135). Prechy-lomicrons are very large and carry a unique cargo comparedwith vesicles that carry nascent proteins (205). Siddiqi et al.(165) showed that chylomicrons are exported from the ER inlarge vesicles (250 nm) by a coat protein complex II (COPII)-independent mechanism, although COPII proteins are found onPCTVs. These investigators demonstrated further that COPII-interacting proteins (Sar1, Sec23/24, and Sec13/31) are neededto form lipid vesicles that can fuse with the Golgi complex.The unique presence of vesicle-associated membrane protein 7in the intestinal ER and on PCTVs has been suggested to play

a role in the export of chylomicrons from the ER to thecis-Golgi (166). Recently, it was shown that an isoform ofprotein kinase C (PKC), PKC, is required for PCTV budding(167). Thus, chylomicrons are transported on unique particles,different from those used for protein transport, by intestinalcells. Similarly, unique particles have been shown to transporthepatic lipoproteins in the liver (164).

Various mechanisms have been shown to regulate the secre-tion of lipoproteins from the intestine. Intestinal lipoproteinproduction is affected by the transcription of apoB, which hasgenerally been believed to be constitutive. Previously, it wasknown that apoB levels change primarily through co- andposttranslational mechanisms; however, Singh et al. (168)

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showed that apoB secretion is affected by a modest change inits transcription. In recent studies, investigators have found thatapoA-IV levels also affect intestinal lipoprotein assembly andsecretion. Increased secretion of nascent TAG and PLs withchylomicrons has been shown in intestinal porcine epithelialcells (a newborn swine enterocyte cell line) overexpressingapoA-IV (114). Similarly, apical supplementation of Caco-2

cells with lipid micelles has been shown to increase apoA-IVmRNA and protein levels, which, in turn, facilitates lipidsecretion (34).

Lipoprotein assembly and secretion is also regulated byMTP, which transfers several lipids and assists in the formationof primordial apoB lipoproteins (87, 90). MTP is modulated byvarious factors and is typically regulated at the transcriptionallevel (68). The initial incorporation of lipids into apoB by MTPprevents it from proteosome-mediated degradation. Geneticdeficiency or pharmacological inhibition of MTP allows con-tinued synthesis of apoB, but the protein is misfolded and isthus destroyed by ER-associated degradation (52, 110). Changesin MTP activity affect plasma apoB lipoprotein levels signifi-

cantly. In an in vitro cell-free system, investigators found thatMTP plays a pivotal role in facilitating lipid recruitment byacting as a chaperone to assist in apoB folding (99). They alsofound evidence suggesting that PL recruitment is intrinsic inthe NH2-terminal domain of apoB during the translationalprocess and may facilitate protein folding. Recently, weshowed that a deficiency in inositol-requiring enzyme 1(IRE1) in mice placed on a high-fat, high-cholesterol dietenhances intestinal MTP expression, which leads to increasedlipid absorption and chylomicron secretion (92). IRE1 wasshown to cause endolytic cleavage of MTP mRNA betweenexons 2 and 7. The cleaved products are subsequently degradedby 3-5 Ski2 nuclease and 5-3-exoribonuclease (XRN)1 andXRN2 exonucleases. Thus, IRE1 decreases MTP mRNA

levels by enhancing its posttranscriptional degradation. Threepotential mechanisms of MTP mRNA degradation have beenproposed: 1) because both IRE1 and MTP mRNA translationare translated within the ER membrane, it is possible that,under the conditions that increase MTP mRNA synthesis (e.g.,high cholesterol and lipid levels), IRE1 and MTP becomejuxtaposed and thus facilitate the specific degradation of MTPmRNA; 2) IRE1 may activate or recruit another nuclease thatinitiates MTP mRNA degradation; or 3) under the conditionsof increased chylomicron assembly, the protein translationalmachinery is temporarily stalled, leading to the recognition ofthe MTP mRNA by endoribonucleases and its subsequentdegradation. IRE1 is a mammalian ER stress sensor protein

with prominent expression within intestinal epithelial cells.Within intestine, IRE1 protein is detectable in the stomach, smallintestine, and colon. Furthermore, it is expressed mainly in theintestinal epithelial cells (15). By modulating MTP mRNA levelsand, consequently, the extent of apoB lipidation, IRE1 may1) protect the ER from the consequences of rapid fluctuations inmembrane PL, neutral lipids, or vitamin E levels or 2) mediatedownregulation of chylomicron secretion in response to satietysignals or respond to endocrine factors released by the liver andadipose tissue in the presence of excess accumulation of lipidthroughout the body. Thus, modulation of IRE1 activity canprovide a way to modulate intestine-specific regulation of lipopro-tein assembly and lipid absorption. In this mechanism, upregula-

tion of IRE1 may be useful for avoiding a diet-induced hyper-lipidemia.

Intestinal lipid absorption has been shown to exhibit diurnalvariations in rodents and humans (8, 23, 118, 129, 143).Although plasma lipid concentrations are maintained within anarrow physiological range, several factors (e.g., plasma clear-ance, cholesterol biosynthesis, and hormonal changes) can lead

to changes in plasma lipids. It was recently demonstrated thatdiurnal variations in plasma lipid levels in rodents are due tochanges in MTP levels (143). Lipid absorption was higher at2400 than at 1200 because of the rodents nocturnal feedingbehavior. Using in situ loops and isolated enterocytes, it wasdemonstrated that circadian variations were due to changes inintestinal activities and not because of variations in gastricfunctions. Further studies have revealed that intestinal expres-sion of MTP also has diurnal variations. Consistent with thisfinding, the transcription rate for microsomal triglyceride trans-fer protein (mttp) was high at 2400 compared with 1200. Thus,it appears that MTP expression and lipid absorption are max-imized to absorb more lipids at mealtime. The diurnal varia-tions in MTP, in turn, may be responsible for the change intotal plasma lipids and apoB lipoproteins (143).

CONCLUSIONS

The absorption of lipids from the intestinal lumen into theenterocytes and their subsequent secretion into circulation is acomplex process. Membrane transporters regulate lipid uptakeon the apical surface of the brush border of the enterocyte. Anessential role for NPC1L1 in cholesterol absorption and for thecoordinated activities of ABCG5 and ABCG8 in limitingexcess cholesterol uptake is well established. Several proteinsinvolved in FA uptake have also been identified. Transport oflipids from the plasma membrane to the ER involves theactivity of intracellular trafficking proteins. Lipids that havebeen absorbed into the ER are resynthesized and packaged intochylomicrons; this process is dependent on apoB and MTPactivity. Specialized vesicles carry these chylomicrons to thebasolateral membrane of the cell for secretion. Posttranscrip-tional degradation of MTP by IRE1 provides a way tomodulate intestine-specific regulation of lipoprotein assemblyand absorption and may be useful for avoiding diet-inducedhyperlipidemias. Recent findings concerning the basolateralefflux of cholesterol as high-density apoA-I-containing li-poproteins will help us identify additional targets for thedevelopment of drugs that may suppress cholesterol absorptionto reduce hypercholesterolemia and the risk for cardiovasculardisease.

GRANTS

This work was supported in part by National Institute of Diabetes andDigestive and Kidney Diseases Grant DK-46700 and a Grant-in-Aid from theAmerican Heart Association to M. M. Hussain.

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