Physiology and pathophysiology of liver lipid metabolismdiplomadoactualidadesendislipidemias.com.mx/...and...lipid_metabol… · KEYWORDS: cardiovascular disease.cholesterol gut microbiota

Physiology andpathophysiology of liver lipidmetabolismExpert Rev. Gastroenterol. Hepatol. Early online, 1–13 (2015)

Francesca RomanaPonziani, Silvia Pecere*,Antonio Gasbarrini andVeronica OjettiInternal Medicine and Gastroenterology,

Agostino Gemelli Hospital, Rome, Italy

*Author for correspondence:

[email protected]

Liver lipid metabolism and its modulation are involved in many pathologic conditions, such asobesity, non-alcoholic fatty liver disease, diabetes mellitus, atherosclerosis and cardiovasculardisease. Metabolic disorders seem to share a similar background of low-grade chronicinflammation, even if the pathophysiological mechanisms leading to tissue and organ damagehave not been completely clarified yet. The accumulation of neutral lipids in the liver is nowrecognized as a beneficial and protective mechanism; on the other hand, lipoperoxidation isinvolved in the development and progression of non-alcoholic steatohepatitis. The role of thegut microbiota in liver lipid metabolism has been the object of recent scientific investigations.It is likely that the gut microbiota is involved in a complex metabolic modulation and thetranslocation of gut microflora may also contribute to maintaining the low-gradeinflammatory status of metabolic syndrome. Therefore, lipid metabolism pathology has vaguelimits and complex mechanisms, and the knowledge of these is essential to guide diagnosticand therapeutic decisions.

KEYWORDS: cardiovascular disease . cholesterol . gut microbiota . liver lipid metabolism . metabolic syndrome . NAFLD. NASH

The liver could be compared with a metabolicbioreactor able to transform lipids, glucoseand various proteins in ready-to-use energeticsubstrates. Albeit these tasks may be carriedout by other tissues too, the hepatocyte givesthe most important contribution to lipid syn-thesis, uptake and export. This continuousturnover of fats has a complex regulation, thedisruption of which is often associated withmetabolic pathologies such as obesity, non-alcoholic fatty liver disease (NAFLD), insulinresistance and diabetes mellitus, atherosclerosisand cardiovascular disease. Despite this com-plex scenario, lipid metabolism is as alwaysinvestigated only in case of clinically evidentdyslipidemia, which is in turn frequentlyinterpreted as an isolated disorder, dependingon dietary habits. However, even if the alter-ation of lipid metabolism is clear in subjectswith serum cholesterol and triglycerides levelsabove the upper limit of normal, it may alsobe present in lean individuals with normallaboratory examinations. Thus, consideringthe high prevalence of concomitant liver andcardiovascular diseases with a high morbidityand to the possibility to modulate completely

or partially the underling metabolic derange-ment, it is crucial to suspect and precociouslyidentify those patients presenting an alteredlipid metabolism. Understanding the physiol-ogy, the pathologic key points and which fac-tors are able to modulate liver lipidmetabolism is mandatory in patient’s diagnos-tic and therapeutic management.

Physiology of liver lipid metabolismLike as a water basin, the hepatic lipid contentis the result of uptake, storage, re-arrangement,outflow and synthesis [1].

Dietary lipids & chylomicrons

In a balanced diet, it is recommended to intro-duce 25–35% of the total daily calories as fatsfrom foods like fish, nuts and vegetable oils,limiting the saturated fats intake to <7% andthe amount of cholesterol to <300 mg [2]. Die-tary lipids are emulsified by bile acids, thenhydrolyzed, absorbed and packaged into chylo-microns (CRs) by the enterocytes (FIGURE 1) [3].CRs enriched in cholesteryl esters, phospholi-pids, triglycerides and the surface proteinApoB-48 are released into lymphatic vessels;

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however, only after the acquisition of ApoC2 and ApoE fromcirculating high-density lipoproteins (HDLs), CRs achieve theirmature shape [4,5]. After lipoprotein lipase (LPL)-mediatedhydrolysis of triglycerides into fatty acids (FAs) in the capillar-ies of adipose and muscle tissue, CRs residuals re-enter into thebloodstream to be taken up by the liver, where the lipid con-tent is further hydrolyzed and used for the synthesis of verylow density lipoproteins (VLDLs) [6,8].

Very low density, intermediate density & low density

lipoproteins

VLDLs are built up from the hepatic lipidation ofApoB-100 with a small amount of triglycerides, phospholipidsand cholesteryl esters [9]. Once released into the bloodstream,VLDLs follow the same route of CRs: they acquire ApoC2 and

ApoE from HDLs, and release free FAs to muscle and adiposetissues after LPL activation (FIGURE 1). At the end of this process,VLDLs transformed in intermediate density lipoproteins areremoved from the bloodstream by the liver (especially thelarger, triglyceride-rich ones); alternatively, after further lipaseactivity, VLDLs may become low-density lipoproteins (LDLs)[10–12]. The uptake of all lipoproteins is mediated by the LDLreceptor (LDLR).

Reverse cholesterol transport

Alongside the flux to and from the liver, lipids are continuouslyexchanged from a lipoprotein to another, in a process knownas ‘reverse cholesterol transport’ (RCT). RCT regulates theremoval of cholesterol overabundance in target tissues, isresponsible of circulating lipoproteins remodeling and is mainly

Dietary lipids

IntestineVLDL

E CB-100

Liver

LDLR

CRs

E B-48CR

B-48

LPL

IDL

E B-100

pre-β-HDL

A1

LDL

B-100

LCAT

HDL

Extrahepaticcells

C2ECapillaries

EC2

Figure 1. Overview of liver lipid metabolism. Lipids deriving from diet, adipose tissue and autophagy are transported to the liver andextrahepatic tissues by lipoproteins with different composition and density. CRs enriched in ApoC2, ApoE and ApoB-48 are released intolymphatic vessels and systemic circulation, hydrolyzed by LPL losing ApoC2, and finally taken up by the liver. VLDLs enriched in ApoC2,ApoE and ApoB-100 follow a route similar to CRs, are transformed in IDLs and removed from the bloodstream by the liver, or alterna-tively become LDLs. In the reverse cholesterol transport, cholesterol and phospholipids are transferred from potentially atherogenic cells(such as macrophages in atherosclerotic plaques) to HDLs (ABCA1-mediated process); dismissed again in systemic circulation, pre-b-HDLsare enriched in cholesteryl esters by LCAT. Finally, cholesterol from lipid-rich HDLs is taken up by the liver and converted into bile acids.Remodeling of circulating lipoproteins is also modulated by CETP, which mediates the exchange of cholesteryl esters inside HDLs for tri-glycerides of LDLs and VLDLs.CETP: Cholesteryl ester transfer protein; CR: Chylomicrons; HDL: High-density lipoproteins; IDL: Intermediate density lipoproteins; LCAT:Lecithin-cholesterol acyltransferase; LDL: Low-density lipoproteins; LDLR: Low-density lipoproteins receptor; LPL: Lipoprotein lipase; VLDL:Very low-density lipoproteins.Adapted from [13,20].

Review Ponziani, Pecere, Gasbarrini & Ojetti

doi: 10.1586/17474124.2015.1056156 Expert Rev. Gastroenterol. Hepatol.

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driven by HDLs synthesized in the liver.HDLs main component is the ApoA1,which binds lecithin-cholesterol acyltrans-ferase, ATP binding cassette A1 (ABCA1)[13] and the scavenger receptor BI (SR-BI)[14,15]. The newborn HDLs have a discoi-dal shape and undergo a multistep pro-cess of maturation exchanging cholesterol,triglycerides, cholesteryl esters with poten-tially atherogenic cells, LDLs and VLDLs(FIGURE 1) [13,16–18]. Finally, cholesterol oflipid-rich HDLs is re-taken up by theliver and converted into bile acids.

Lipogenesis

Part of the hepatic pool of FAs derivesfrom de novo synthesis, starting fromacetyl-CoA and ending with the production of the 16-carbon pal-mitic acid, which can further be desaturated and/or elongated [19].FAs are used to synthesize glycerolipids (phospholipids: mono-,di- and triglycerides, which are relatively inert) and cholesterol.This process takes place in the liver in a quantitatively more effi-cient way than in the adipose tissue and is regulated by variousnuclear receptors (PPAR-a and -g and the bile acid receptor/farnesoid X receptor [FXR]) [20–23]. The expression of HMG-CoA reductase (the limiting step of cholesterol synthesis) as wellas LDLR synthesis are negatively controlled by intracellular cho-lesterol. Cholesterol production is also regulated by the sterol reg-ulatory element binding proteins (SREBP), which bind thenuclear sterol response element (SRE) when cells are depleted ofsterols, activating the transcription of genes involved in choles-terol synthesis [24,25]. SREBP-1c is the major isoform expressed inthe liver and has overlapping functions with another protein ofthe family, SREBP-2; however, the former activates the transcrip-tion of genes regulating fatty acid biosynthesis, and the latter ismore involved in the modulation of cholesterol metabolism [25].Glucose is another trigger for lipogenesis via the glycolytic path-way or via the activation of the carbohydrate responsive elementbinding protein/carbohydrate responsive element pathway in theliver cells. High carbohydrates diet leads to the transcription ofvarious lipogenic enzymes genes, increase in HDLs levels and tohypertriglyceridemia [20,26–29]. In contrast, polyunsaturated FAsdecrease lipogenesis by suppressing gene expression in murineliver [30]. Finally, cholesterol synthesis is regulated by circadianrhythm, being two- to threefold higher during the dark phase ofthe light cycle, with a peak in synthesis several hours afterfeeding [31–33].

Lipid distribution & storage

Lipids produced by the liver are then included in lipoproteinsand carried out to other tissues to be used as source of energyand structural components; triglycerides can also be stored inlipid droplets that are the main form of hepatic fat accumula-tion [34]. Lipid droplets are considered as dynamic cellularorganelles rather than simple lipid storage depots; they originate

between the leaflets of endoplasmic reticulum (ER) bilayer, aresecreted in the cytosol and take contact with mitochondriawhen hydrolysis of triglycerides is needed to supply metabolicdemand [35,36]. In this way, the excess of lipids and FAs areneutrally stored into lipid droplets, keeping low the intracellu-lar concentration of potentially lipotoxic intermediates [36].

b-Oxidation

FAs derived from recycled cellular components or from thecatabolism of circulating lipoproteins and triacylglycerols storedin the adipose tissue are carried to the liver by specific trans-porters (fatty acid transport proteins) [37,38]. The part of themthat is not used to form lipoproteins is channeled towardsb-oxidation to produce energetic substrates [27]. As first, theyare converted into acyl-CoA by the cytosolic enzyme acyl-CoAsynthetase; however, acyl-CoA cannot be directly transferredinto mitochondria, the transport being mediated by the carni-tine shuttle. This is an important regulation point of b-oxida-tion, which is up- or downregulated in conditions of starvationor feeding, respectively. In the mitochondria, acyl-CoA is ulti-mately converted into acetyl-CoA for the Krebs (tricarboxylicacid) cycle or used to produce ketone bodies [39,40].

NAFLD & liver lipid metabolismNAFLD is not simply a liver pathology having only local con-sequences (fibrosis/cirrhosis), but is part of the large network ofmechanisms involved in cardiovascular disease.

Since the existence of a particular phenotype more prone todevelop cardiovascular events was acknowledged, criteria toimprove patient’s clinical framework have been constantlyimplemented. However, ‘metabolic syndrome’ is still the favor-ite definition to encompass all individuals with metabolicderegulation. The typical patient with metabolic syndrome hasincreased fasting plasma glucose or type 2 diabetes, hypertrigly-ceridemia, low HDL cholesterol, increased waist circumferenceand hypertension (TABLE 1) [41–43]. He (or she) is often obese andsedentary, with hepatic insulin resistance and increased trigly-cerides accumulation in the liver [41–43].

Table 1. Criteria for the diagnosis of metabolic syndrome.

Risk factor Cut points

Abdominal obesity (waist circumference)

Men >102 cm (>40 in.)

Women >88 cm (>35 in.)

Triglycerides ‡ 150 mg/dl

High-density lipoprotein cholesterol

Men <40 mg/dl (1.0 mmol/l)

Women <50 mg/dl (1.3 mmol/l)

Blood pressure Systolic ‡130/85 mmHg and/or diastolic ‡85 mmHg

Fasting glucose ‡100 mg/dl

Adapted from [41].

Physiology & pathophysiology of liver lipid metabolism Review

informahealthcare.com doi: 10.1586/17474124.2015.1056156

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Taking a look inside realty, NAFLD represents a health prob-lem for 30% of the general adult population and for 70–80% ofdiabetic and obese patients [44], who therefore have an alteredliver lipid metabolism. Notwithstanding, it is possible to identifylean subjects with NAFLD, who should therefore be consideredas ‘metabolically obese’ individuals with normal weight. Some-times these subjects have a history of recent or progressive weightgain; more generally, their energy intake exceeds energy expendi-ture and could probably be the first step toward the developmentof NAFLD [45]. Therefore, obese or less frequently lean individu-als with insulin resistance have an impaired inhibition of hepaticglucose production during fasting, which leads to mild hypergly-cemia, increased insulin secretion and hyperinsulinemia [46];when b-cells compensating activity becomes unable to sustaininsulin secretion, overt hyperglycemia of type 2 diabetesappears [46]. Like metabolic syndrome, NAFLD is associated withboth type 2 diabetes and cardiovascular disease [47–49].Reciprocally, metabolic syndrome is an important predictor ofnon-alcoholic steatohepatitis (NASH) [47,50–53]. Although it isunknown what comes first, the accumulation of lipids in the liveror insulin resistance, post-prandial hyperinsulinemia isunquestionably a regulator of hepatic lipogenesis [54].

Lipid metabolism in NAFLD

Patients with NAFLD typically present a pro-atherogenic lipidmetabolism, characterized by high levels of VLDLs, reducedlevels of HDLs and increased LDL concentrations, even inabsence of high LDL-cholesterol levels [55].

The aforementioned alterations are associated with hyperin-sulinemia. Insulin increases lipolysis and FAs transport to theliver, enhances hepatic lipogenesis but suppresses VLDLssecretion (FIGURE 2) [55].

Several studies in NAFLD patients have demonstrated anincreased hepatic uptake of FAs from peripheral adipose tissueand an increased de novo lipogenesis, which are not balancedby FAs oxidation and VLDLs production causing hepatic try-glicerides accumulation [31,33].

Hepatic LPL is upregulated in presence of insulin resistanceand NAFLD, increasing the production of small denseLDLs [56–58]. Furthermore, LDLR expression is reduced in theliver, increasing the number of circulating LDLs that is a typi-cal feature of atherogenic dyslipidemia.

Finally, hyperinsulinemia decreases HDLs synthesis and theiruptake is more rapid, with the reduction in overall effect ofplasmatic HDLs levels [59,60].

Increasedlipogenesis

Adipocytes

LDLR

Decreasedβ-oxidation

FA

Increasedlypolisis

Lipiddroplets

Esterification

Decreasedsecretion

VLDLs

TG TG

NEFA

TGTGTGDecreasedsynthesis

Increasedcirculating

number

Decreasedexpression

LDLs

Hyperglycemiahyperinsulinemia

HDLs

Figure 2. Liver lipid metabolism is altered in patients with NAFLD, mostly due to insulin resistance. Insulin suppresses VLDLssecretion, stimulates lipolysis in adipose tissue and lipogenesis in the liver and increases the expression of the hepatic FATP caveolins,CD36 and FABP. FAs excess is used for the synthesis of triglycerides, which are stored as lipid droplets in the hepatocytes or secretedwithin VLDLs. Hyperinsulinemia reduces LDLR expression in the liver, increasing the number of circulating LDLs and decreases HDLs syn-thesis due to the increased degradation of ABCA. CETP activity is enhanced by producing triglyceride-enriched HDLs, which are more rap-idly taken up by the cells, reducing levels of HDL cholesterol. The overall result is a pro-atherogenic lipid metabolism, characterized byhigh circulating levels of VLDLs, reduced levels of HDLs and increased LDL concentrations even in absence of high LDL-cholesterol levels.FA: Fatty acid; HDLs: High-density lipoproteins; LDLR: Low-density lipoproteins receptor; LDLs: Low-density lipoproteins; NEFA: Non-esterifiedfatty acid; TG: Triglyceride; VLDLs: Very low-density lipoproteins.Adapted from [55,60,114,153–157].



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Natural history of NAFLD & NASH

As previously discussed, disorders of liver lipid metabolism andfeatures of metabolic syndrome identify the same patient havingan increased risk of cardiovascular events. It is not surprising thatNASH and metabolic syndrome share a similar pathologic back-ground of ‘low grade’ chronic inflammation, also called‘metainflammation’ [61–63]. However, this apparently perfect over-lap between metabolic syndrome and NAFLD should be consid-ered carefully. Revising the scientific production of the recentyears, too many definitions of metabolic syndrome and too manymethods of diagnosing NAFLD make it difficult to definitivelydraw any conclusion. Furthermore, NAFLD is a pathology withtwo different faces. Indeed, NAFL is characterized by the simpleaccumulation of triglycerides in the liver, whereas inflammatorydamage is the main feature of NASH, which therefore representsthe worst type of NAFLD. The first hypothesis of a ‘two hits’model, beginning with lipid accumulation in the liver (non-alco-holic fatty liver, NAFL, first hit) and further progressing towardfibrosis and cirrhosis due to liver inflammation and damage(NASH, second hit) [64], has recently been replaced by a multiple‘parallel hits’ model. Accordingly, the simple accumulation of fatin the liver has recently changed its prognostic significance, andis now considered as a non-progressive condition, well separatedfrom NASH and no more as its precursor [65]. In other words,NAFL and NASH follow two distinct ways, inflammation, lipo-toxicity and fibrosis (recognizable in NASH since the beginning)being the main differences [34,65].

Cellular mechanisms driving liver injury & disease

progression

What is the role of lipid accumulation in the liver, and whichis the trigger for inflammation in NASH? To answer thesequestions, it should be considered that fats are not equal toeach other. Indeed, the simple accumulation of triglyceridesand cholesterol esters has no pathologic effects on the liver, butis rather a defensive mechanism to avoid the accumulation oftoxic lipids, such as free FAs, diacylglycerides, phospholipids(ceramides, sphingolipids) and free cholesterol [34,62–69]. In par-ticular, scientific research focused on FAs. As previously dis-cussed, FAs derive from adipose tissue, de novo lipogenesis orlipolysis/autophagy [70]; patients with NAFLD have anincreased availability of circulating FAs and their uptake by theliver is facilitated too [70–73]. Genetic factors are also involvedin this mechanism; the single nucleotide polymorphismrs738409 in the human patatin-like (phospholipase domaincontaining 3 or adiponutrin) gene has been recently associatedwith NAFL, inflammation and fibrosis, independently of bodymass, insulin resistance and serum lipid levels [74]. Phospholi-pase domain containing 3 is expressed in the liver and has tri-glyceride hydrolase and diglyceride transacylase activity, whichare altered in presence of the polymorphism causing the accu-mulation of lipotoxic substrates [75–77].

In this condition of FAs abundance, mitochondria areoverloaded and peroxisomes and ER become sites ofoxidation [78,79].

Crosstalk between lipid accumulation, inflammation &

apoptosis

NASH is characterized by mitochondrial dysfunction, ER stressand reactive oxygen species (ROS) formation, resulting in theactivation of inflammatory pathways. Abnormal mitochondrialfunction has been reported by several studies and mitochondrialmetabolism is accelerated in NAFLD by 50 and 30% asregards lipolysis and gluconeogenesis, respectively [80–84]. Invitro experiments have confirmed that the increased mitochon-drial activity consequent to the FAs hyper-afflux is responsiblefor ROS production and precedes the activation of apoptosispathway in liver cells [85]. However, other studies seem to ques-tion the correlation between b-oxidation and ROS production;probably, lipids are not simply substrates for increased oxidativemetabolism but may exert other regulatory effects on mito-chondrial function [85–87]. Furthermore, the oxidative stressassociated with NASH has been attributed to upregulated levelsof cytochrome P450 2E1 and NADPH oxidase [88,89].

ER stress is another feature of patients with NAFLD [90–92].Abnormal incorporation of saturated phospholipids in ERmembrane may cause loss of functionality, activate unfoldedprotein response stress signaling pathway and disrupt mito-chondrial function [93]. Indeed, unfolded protein response isprotectively involved in the degradation of misfolded proteins,but in case of excessive and prolonged stress it can trigger apo-ptosis via Janus kinases signaling and the release of calcium byER [94,95]. Calcium is then taken up by mitochondria, trigger-ing other apoptosis signals [94,96–98].

Inflammation is the final result of this deranged intracellularequilibrium. FAs may activate NF-kB signaling directly and viaER stress and mitochondria deregulation, inducing transcrip-tional upregulation of proinflammatory cytokines, such as IL-6,TNF-a and its receptor [99–104]. Higher serum levels of TNF-aand soluble TNF-a receptor 2 (TNFR2) have been found inpatients with NASH compared with healthy subjects [105].Interestingly, while no significant variation has been detected inserum levels of TNF-a and soluble TNFR2, differences intheir hepatic expression have been found comparing NAFL andNASH patients and TNF-a plasma levels have been directlyrelated to liver fibrosis grade [100,105,106]. Finally, IL-6 is overex-pressed in the liver and in the serum of patients with NASH ifcompared with healthy controls [107,108].

Other stimuli take part in the pathogenesis of NASH, andmost of them, called ‘adipokines’, are derived from the adiposetissue. TNF-a and IL-6 production is increased in the adipo-cytes of obese human subjects and of patients with insulinresistance contributing to the overall pool of released cyto-kines [109,110]. Conversely, adiponectin and leptin levels, the twoadipokines having a protective role on inflammation and lipo-toxicity, are reduced [111,112]. In particular, tissues are resistantto leptin; thus, food intake is increased but energy expenditureremains constant, favoring ectopic lipid storage [113,114]. Theanti-inflammatory and antidiabetic effects of adiponectin areimpaired in NASH patients. Indeed, adiponectin serum levelsare lower in patients with NASH than in matched controls;



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similarly, the expression of adiponectin mRNA and its specificreceptor ADIPOR2 are lower in patients with NASH com-pared with those with NAFL [106,115]. Adiponectin/ADIPOR2system deregulation has been associated with steatosis and nec-roinflammation, but data about a possible correlation with liverfibrosis are contrasting [106,115].

PPARg is an important modulator of lipid storage, exert-ing anti-inflammatory and anti-fibrotic effects on stellatecells, macrophages and epithelial cells [116]. PPARg expressionis increased in steatotic livers [117]. Treatment with PPARgagonists has been demonstrated beneficial on hepatic steato-sis, probably due to increase in insulin sensitivity of adiposetissue and skeletal muscle, indirectly leading to a reductionin FAs deposition in the liver [116]. Adiponectin activity isstrictly linked to PPARs: it is upregulated by PPARg and,in turn, is able to upregulate PPARa expression, which inturn stimulates energy expenditure through hepatic FAoxidation [116].

Cannabinoid receptors (CB1 and 2) and endocannabinoidsactivity are upregulated in liver injury and have been reportedto be involved in the development of liver fibrosis [118].CB1 production is enhanced in experimental models ofNAFLD, stimulating SREBP1c-mediated lipogenesis, reducingFAs b-oxidation and VLDLs secretion by the liver, increasingrelease of FAs by the adipose tissue and decreasing adiponectinproduction [119–122].

Finally, visfatin, a protein secreted by activated lymphocytes,seems to have a protective role in NASH pathogenesis, but thisneeds to be further investigated [123].

Gut microbiota & liver lipid metabolismPhysiology of gut microbiota lipid metabolism & its

pathologic implications

Part of the hepatic lipid pool derives from the gut, and gutmicrobiota is a well-known regulator of liver lipid turnover.A lot of microbes are present within the gut, with a progres-sively increasing gradient from the stomach to the small andthe large intestine [124]. Duodenum and jejunum are the mainsites of lipid absorption, and host bacteria concentrations ofabout 10 [4] colony-forming units per gram of luminalcontent [124].

Lipids are fuel for microbes. Indeed, conventional mice bear-ing a normal microbiota have an increased production of lipidmetabolites such as pyruvic, citric, fumaric and malic acidwhen compared with germ-free mice [125]. However, gut micro-biota is not a simple ‘buffer’, which reduces plasma levels ofcholesterol and other lipids by converting them in highly ener-getic substrates [125]. A more complex scenario has been recentlyhighlighted, the key-point of which is the metabolic potentialof gut microbiota (gut metaboloma). Backhed et al. [126]

reported a 60% increase in body fat content, a 2.3-fold increasein hepatic triglycerides and the development of insulin resis-tance despite reduced food intake in germ-free mice after gutcolonization. The simplest explanation is the acquired capacityof a particular gut microbiome for energy harvest [127]. In a

subsequent study [126], the same authors reported a similarenergy content in stool samples of germ-free and conventional-ized mice. In that experiment, microbial colonization of thegut was demonstrated to modulate hepatic and adipose tissuelipogenesis increasing ChreBP and SREBP-1, and suppressingintestinal secretion of fasting-induced adipose factor, an inhibi-tor of LPL in the adipose tissue. Moreover, conventional micehad a reduced FAs b-oxidation, both mediated by fasting-induced adipose factor-PPAR1a, and a reduced adenosinemonophosphate-activated protein kinase activity [126]. The factthat obesity-associated phenotypes and body mass were trans-missible with fecal microbiota transplantation, and that miceco-housing was able to prevent these changes, definitively con-firmed the connection between microbiota and fat metabolism[127,128].

More recent metagenomic and metabolomic studies demon-strated that gut microbiota may convert dietary choline intohepatotoxic methylamines (dimethylamine, trimethylamine andtrimethylamine N-oxide; FIGURE 3); consequently, the assemblyand secretion of VLDLs, of which choline is a structural com-ponent, is reduced and hepatic lipid accumulation increases,together with lipoperoxidation [129,130]. Notably, fatty liver isassociated with disruption of choline metabolism, and choline-deficient diets are used to reproduce NAFLD models [130,131].Furthermore, elevated levels of choline, trimethylamine N-oxideand betaine have been demonstrated to be associated with thepresence of cardiovascular disease, an evidence that gives to gutmicrobiota a more precise collocation in the picture of meta-bolic syndrome and its pathologic correlates [132]. Finally, gutmicrobiota may modulate hepatic and systemic fat storage bymodifying bile acids structure, interfering with their functionin lipid absorption and with their indirect impact onlipoperoxidation [133].

Role of gut microbiota in NAFLD: dysbiosis, altered

intestinal permeability & bacterial translocation

Beside the recent evidences of their metabolic activity,microbes have historically been related to inflammation, andinflammation is the main feature of NASH. Microbial prod-ucts and components (microbes-associated molecular patterns,pathogen-associated molecular patterns) or products of tissuedamage (damage-associated molecular patterns) are usuallyrecognized by pattern recognition receptors, which areexpressed by enterocytes and hematopoietic cells and mediatethe interactions between the immune system and gutmicrobiota (FIGURE 3) [134]. In physiologic conditions, the recog-nition of microbes-associated molecular patterns such as lipo-polysaccharide, lipid A, peptidoglycan, flagella and microbialRNA/DNA by Toll-like receptors and nuclear oligomerizationdomain-like receptors lead to a tolerogenic downstream sig-naling pathway [134]. This is how the gut ‘senses’ the micro-biota, and is crucial for maintaining immunologichomeostasis [135]. This balance is broken in patients withNAFLD. An increased plasma LPS concentration has beendescribed in mice on high-fat diet developing fatty liver and



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endotoxemia was linked to increased intestinal permeabil-ity [136,137]. Antibiotics reduce metabolic endotoxemia, theaccumulation of fat in the liver and inflammation [137,138].Studies conducted in humans reported a high prevalence ofsmall intestinal bacterial overgrowth and increased intestinalpermeability in patients with NASH, together with alteredmicrobiota composition and increased circulating proinflam-matory cytokines [100,139–142]. It has been hypothesized thatabnormal translocation of bacteria and endotoxins in the por-tal circulation to the liver due to leaky gut activates Toll-likereceptors signaling and NF-kB, with the consequent tran-scription of genes encoding inflammatory cytokines, chemo-kines and antimicrobial agents [143–145].

In addition, other cytoplasmic complexes called‘inflammasomes’ have been involved in NASH pathogene-sis [146]. Inflammasomes are composed of NLRs, the proteinAsc and the effector protein caspase-1; when sensing pathogen-associated molecular patterns and damage-associated molecular

patterns, pro-IL-1b and pro-IL-18 are processed leading to therelease of biologically active cytokines. InflammasomesNLRP6 and NLRP3 negatively regulate NASH progression bychanging the gut microbiota composition and reducing hepaticTNF-a expression [146].

It has also been demonstrated that the adipose tissue produ-ces more proinflammatory cytokines compared with the liverin patients with NAFLD [65]. Burcelin and collaborators [147]

fascinatingly reported that adipose tissue and blood from dia-betic mice fed with HFD contain live bacteria, which origi-nate from intestine and are linked to low-grade inflammation.Thus, gut microbiota may translocate and induce local inflam-mation in the adipocytes but also in the liver, heart, vesselsand other various tissues realizing a kind of ‘metabolicinfection’ (FIGURE 3).

Gut microbiota is also able to produce ethanol increasinginflammation and hepatotoxicity [148]; higher systemic ethanollevels have been found in patients with NASH [148].

Dietarycholine

Choline

ChREBP/SREBP-1

TMA

gut flora

MAMPs,PAMPs,DAMPS

Increasedgut permeability

Leaky gut

NLRs

PRRs

TLRsLeaky andinflamed

Normal tight

junction

Intestinalmucosal cells

Blood stream

TMAO

Adipose tissue

Atherosclerosis

VLDL

Metabolic infection

Inflammation

FAs

LPL

Fiaf

CRs

LPS absorption

Metabolicendotoxemia

Figure 3. The gut microbiota is involved in liver lipid metabolism by several mechanisms. Production of proatheroscleroticmetabolites from dietary choline such as trimethylamine; the abnormal translocation of bacteria and endotoxins due to leaky gut andincreased intestinal permeability with the activation of TLRs signaling and NF-kB, with consequent transcription of genes encoding inflam-matory cytokines, chemokines and antimicrobial agents leading to local and systemic inflammation (metabolic infection); the stimulationof hepatic lipogenesis through suppression of Fiaf, the activation of ChREBP/SREBP-1 and the increase of LPL activity in adipocytes.ChREBP: Carbohydrate responsive element binding protein; CR: Chylomicrons; DAMP: Damage-associated molecular patterns; FAs: Fattyacids; Fiaf: Fasting-induced adipose factor; LPL: Lipoprotein lipase; MAMP: Microbes-associated molecular patterns; NLRs: Nuclear oligomer-ization domain-like receptor; PAMP: Pathogen-associated molecular patterns; PRRs: Pattern recognition receptors; SREBP-1: Sterol regula-tory element binding protein-1; TLRs: Toll-like receptors; TMA: Trimethylamine; TMAO: Trimethylamine N-oxide; VLDL: Very low-densitylipoproteins.



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Expert commentaryIn Western countries, pathologies connected to lipid metabo-lism cause more death and disability than all types of cancercombined [149–152].

It is interesting to consider how the liver plays a central rolein lipid metabolism, and that its function is not a mere resultof a series of enzymatic reactions. Lipid metabolism is finelyregulated by various inputs, depending on the energy status ofthe whole body and on the quality and quantity of food intake,deriving from the tissues mainly involved in energy storage andutilization (adipose tissue, muscle) and from microbes residentin the gut. Furthermore, diseases related to lipid metabolismare typically not restricted to a single target organ, but ratherpresent a shared phenotype and should not be considered inde-pendent from the other. The explanation is due to the pivotalrole of inflammation as common precipitating trigger, which isrecognizable in NASH as well as in atherosclerosis, insulinresistance and diabetes. Lipid metabolism pathology has there-fore vague limits and mechanisms overlapping with other meta-bolic and cardiovascular disorders in the same individual,nevertheless presenting inter-individual similarities.

Five-year viewThe progress in understanding lipid liver metabolism patho-physiology, especially as regards cellular mechanisms drivingliver injury and disease progression, and the crosstalk betweenlipid accumulation, inflammation and apoptosis will be thebackground to develop new therapeutic strategies. Newmolecules targeting specific cytokines-associated pathways or

stimulating the production of beneficial adipokines such as lep-tin and adiponectin should be the future therapeutic scenarioin the management of NASH. The first steps in this directionhave recently been made by pre-clinical and clinical studiesinvestigating the use of PPAR agonists in the treatment ofNAFLD.

The increasing importance of gut microbiota in the modula-tion of host metabolism is certainly a stimulating innovativefinding of the recent literature. It will open new frontiers totherapy and put into different light the initiation and the evo-lution of metabolic disorders; for example, probiotics and pre-biotics effects in the treatment of NAFLD are source of greatscientific interest and are still under study.

In the future, clinicians should acquire a holistic approach tometabolic pathologies. In this new scenario, liver is not so dis-tant from the heart, and both are not independent of the intes-tine. This fascinating concept is essential in the management ofpatients with metabolic syndrome, cardiovascular diseases, dia-betes and NAFLD, and should drive the approach to thepatient towards a more integrated program of diagnostic andtherapeutic decision.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with

any organization or entity with a financial interest in or financial con-

flict with the subject matter or materials discussed in the manuscript.

This includes employment, consultancies, honoraria, stock ownership or

options, expert testimony, grants or patents received or pending or

royalties.

Key issues

. The hepatic lipid content is the result of uptake, storage, re-arrangement, outflow and synthesis, finely regulated by complex metabolic

mechanisms.

. The pathology of liver lipid metabolism has not only local consequences (fibrosis/cirrhosis), but is part of a large network involving

insulin resistance and linked to cardiovascular pathology.

. Non-alcoholic fatty liver disease represents a health problem for 30% of the general adult population and for 70–80% of diabetic and

obese patients, who therefore have an altered hepatic lipid metabolism.

. Metabolic syndrome and non-alcoholic fatty liver disease share a similar pathologic background of low-grade chronic inflammation.

. Non-alcoholic fatty liver and non-alcoholic steatohepatitis (NASH) are well-distinct manifestations of deregulated hepatic lipid

metabolism, inflammation, lipotoxicity and fibrosis (recognizable in NASH since the beginning) being the main differences.

. Lipoperoxidation and the consequent accumulation of reactive oxygen species are the main causes of FA-related toxicity; hepatic

cytokines and adipokines such as IL-6, TNF-a, leptin, adiponectin, PPARs and the endocannabinoid system are involved in the develop-

ment of NASH and its progression.

. Gut microbiota is involved in the metabolism of dietary choline, which is a structural component of lipoproteins, thus affecting the

secretion of VLDLs and promoting hepatic lipid accumulation, lipoperoxidation and insulin resistance.

. Gut microbiota may modulate hepatic and systemic fat storage by modifying bile acids structure, thus interfering with their function in

lipid absorption and with their indirect impact on lipoperoxidation.

. Gut microbiota translocation induces local inflammation in the liver but also in the adipocytes, heart, vessels and others various tissues,

realizing a kind of metabolic infection, which might contribute to the low grade inflammatory status characterizing metabolic

syndrome.



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Physiology and pathophysiology of liver lipid metabolismdiplomadoactualidadesendislipidemias.com.mx/...and...lipid_metabol… · KEYWORDS: cardiovascular disease.cholesterol gut microbiota