Evolution of Inflammation in Nonalcoholic Fatty Liver Dia:The Multiple Parallel Hits Hypothesis
Herbert Tilg and Alexander R.Moschen
Whereas in most cas a fatty liver remains free of inflammation,10%-20%of patients
周国who have fatty liver develop inflammation andfibrosis(nonalcoholic steatohepatitis
[NASH]).Inflammation may precede steatosis in certain instances.Therefore,NASH
could reflect a dia where inflammation is followed by steatosis.In contrast,NASH sub-
quent to simple steatosis may be the conquence of a failure of antilipotoxic protection.
In both situations,many parallel hits derived from the gut and/or the adipo tissue may
promote liver inflammation.Endoplasmic reticulum stress and related signaling networks,
(adipo)cytokines,and innate immunity are emerging as central pathways that regulate key
features of NASH.(H EPATOLOGY2010;52:1836-1846)
N onalcoholic fatty liver dia(NAFLD) includes a dia spectrum ranging from
simple steatosis to nonalcoholic steatohepati-tis(NASH),liverfibrosis,cirrhosis,and hepatocellular carcinoma.1The majority of patients with NAFLD are obe or even morbidly obe and have accompanying insulin resistance.2-4The proportion of patients with NAFLD who have NASH is still not entirely clear but might range from10%-20%.This is relevant becau inflammation and/orfibrosis determine the long-term prognosis of this dia,whereas steatosis per might not adverly affect outcome.5-8Most studies indicate that1%-3%of the Western population might have NASH.The natural history of NAFLD is still poorly understood,and in particular,it is not known why cer-tain patients progress toward inflammation,fibrosis, and cirrhosis and why others do not.One of the burn-ing questions in NAFLD remains which factors could be the driving forces toward a more progressive, inflammatory dia phenotype.Day and colleagues prented more than a decade ago the so-called‘‘two-hit’’model,suggesting that after afirst ,hepatic steatosis)another ,gut-derived endotoxin)is needed to develop NASH.9刘明欣
两个明确Becau simple hepatic steatosis is a benign process in the majority of patients,NASH might be a parate dia with a different pathogenesis.Here,we propo a new model suggesting that many hits may act in par-allel,finally resulting in liver inflammation and that especially gut-derived and adip
o tissue–derived fac-tors may play a central role.Inflammation may pre-cede steatosis in NASH,as inflammatory events may lead to subquent steatosis.Furthermore,we want to highlight the potential importance of endoplasmic reticulum(ER)stress in various aspects of this dia. Development of Hepatic Steatosis
A fatty liver is the result of the accumulation of var-ious lipids.10Several mechanisms may lead to a fatty liver:(1)incread free fatty acids supply due to incread lipolysis from both visceral/subcutaneous adi-po tissue and/or incread intake of dietary fat;(2) decread free fatty oxidation oxidation;(3)incread de novo hepatic lipogenesis(DNL)and(4)decread hepatic very low density lipoprotein–triglyceride cre-tion.11Free fatty acid delivery to the liver accounts for almost two-thirds of its lipid accumulation.12
Abbreviations:AhR,aryl hydrocarbon receptor;ATF-6,activating transcription factor6;ChREBP,carbohydrate respon element-binding protein; DGAT,diacylglycerol acyltransfera;DNL,de novo lipogenesis;ER, endoplasmic reticulum;IKK b,inhibitor of nuclear factor-j B kina-b;Gpr,G protein–coupled receptor;IL,interleukin;IRE1,inositol-requiring enzyme1; JNK1,c-jun N-terminal protein kina1;LPS,lipopolysaccharide;mRNA, mesnger RNA;PERK,pancreatic ER kina;PI3K,phosphatidyl inositol3-kina;patatin-like phospholipa3PN
PLA3;PPAR c,peroxisome proliferator-activated receptor-gamma;ROS,reactive oxygen species;SCFA,short chain fatty acid;SOCS3,suppressor of cytokine signaling3;SREBP,sterol regulatory element-binding protein;TLR,toll-like receptor;TNF,tumor necrosis factor; UDCA,ursodeoxycholic acid;UPR,unfolded protein respon;XBP1,X-box binding protein1.
From the Christian Doppler Rearch Laboratory for Gut Inflammation, Medical University Innsbruck,Innsbruck,Austria
Received July11,2010;accepted September13,2010.
This work was supported by the Christian Doppler Rearch Society. Address reprint requests to:Herbert Tilg,M.D.,Christian Doppler Rearch Laboratory for Gut Inflammation,Medical University Innsbruck,Anichstras 35,6020Innsbruck,Austria.E-mail:herbert.tilg@i-med.ac.at;fax:þ43512 5046723374.
Copyright V C2010by the American Association for the Study of Liver Dias. View this article online
DOI10.1002/hep.24001
怎样做羊肉汤
Potential conflict of interest:Nothing to report.
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Elevated peripheral fatty acids and DNL therefore pre-dominantly contribute to the accumulation of hepatic fat in NAFLD.Besides the well-established lipogene-sis-controlling factors such as sterol regulatory ele-ment-binding protein(SREBP)or carbohydrate respon element-binding protein(ChREBP),X-box binding protein1(XBP1),known as a key regulator of the unfolded protein respon(UPR)condary to ER stress,is a only recently characterized regulator of hepatic lipogenesis.13
T riglycerides are the main lipids stored in the liver of patients with NAFLD.Although large epidemiological studies suggest triglyceride-mediated pathways might negatively affect dia,14recent evidence indicates that trigylcerides might exert protective functions.Diacyl-glycerol acyltransfera1and2(DGAT1/2)catalyze the final step in triglyceride synthesis.In a model of diet-induced obesity,mice with overexpression of DGAT1in adipocytes and macrophages are protected from macro-phage activation and their accumulation in white adi-po tissue,from systemic inflammation and insulin re-sistance.15Inhibition of triglyceride synthesis via DGAT2antin
oligonucleotides improves liver steato-sis but worns liver damage,also suggesting that accu-mulation of liver triglycerides could be a protective mechanism.16Hepatic ,triglyceride accu-mulation)is dissociated from insulin resistance in patients with familial hypobetalipoproteinemia,provid-ing further evidence that incread intrahepatic triglycer-ide content might be more a marker rather than a cau of insulin resistance.17In summary,triglyceride synthesis ems to be an adaptive,beneficial respon in situations where hepatocytes are expod to potentially toxic tri-glyceride metabolites.Thus,evidence is increasing that accumulation of fat in the liver in many instances cannot be regarded as a pathology or dia,but rather as a physiologic respon to incread caloric consumption.18 Free fatty acids and cholesterol,especially when accumulated in mitochondria,are considered the ‘‘aggressive’’lipids leading to tumor necrosis factor alpha(TNF a)-mediated liver damage and reactive oxy-gen species(ROS)formation.19,20The lipids could also be prent in a nonsteatotic liver and act as early ‘‘inflammatory’’hits leading to the whole spectrum of NAFLD pathologies.The concept of lipotoxicity and involved lipid species has been introduced and dis-cusd in veral excellent review articles.21,22
Inflammation Preceding Steatosis.Simple hepatic steatosis,which is benign and nonprogressive in the ma-jority of patients,and NASH may reflect different dis-ea entities.Inflammation results in a str
ess respon of hepatocytes,may lead to lipid accumulation,and there-fore could precede steatosis in NASH.Such a cascade is supported by various studies.Patients with NASH may prent without any or much steatosis,suggesting that inflammation could take placefirst.1Anti-TNF anti-body treatment and metformin,an antidiabetic drug that inhibits hepatic TNF a expression,improve steatosis in ob/ob mice.23,24Other proinflammatory mediators might also contribute to the development of steatosis becau in some studies hepatic steatosis was not de-pendent on TNF a.25,26In patients with vere alcoholic hepatitis,treatment with infliximab,an anti-TNF anti-body,primarily improves hepatic steatosis.27Loss of Kupffer cells also leads to hepatic steatosis probably via decread interleukin-10(IL-10)relea from Kupffer cells.28Other cell types might also promote hepatic ste-atosis becau obesity leads to the hepatic recruitment of a myeloid cell population that further promotes hepatic lipid storage.29In all the situations,hepatic steatosis may be considered as‘‘bystander phenomenon’’sub-quent to inflammatory attacks.Very diver process including toxic lipids,nutrients,and other gut-derived and adipo-derived signals(as discusd later)may rep-rent such inflammatory insults.
Certain Dietary Factors:A Direct Roadmap to Lipotoxic-ity?The consumption of trans-fatty acids has incread dramatically in the last decades and mice fed trans-fatty acids develop larger livers with N
ASH-like lesions and in-sulin resistance.30Although virtually abnt from our diet in the past,fructo has now become a major constituent of modern diet.When obe subjects consumed gluco-or fructo-sweetened beverages for10weeks,fasting plasma gluco and insulin levels incread and insulin nsitivity decread in subjects consuming fructo but not in tho consuming gluco.31Daily fructo con-sumption is associated with incread hepatic inflamma-tion andfibrosis in humans.32The aryl hydrocarbon receptor(AhR)is a ligand-activated transcription factor nsing xenotoxicants such as dioxin.This pathway may play a major role in inflammatory process.33Many AhR agonists are prent in the diet such as indolo-(3,2-b)-carbazole and3,30-diindolylmethane(metabolized from indole3-carbinol),orflavonoids.T ransgenic mice with constitutively activated AhR develop spontaneous hepatic steatosis and incread hepatic oxidative stress.34 It remains to be identified how certain nutrients might directly lead to liver inflammation.
Gut-Derived Signals Beyond Endotoxin May Promote Liver Inflammation Conventionalization of germ-free mice with a nor-mal microbiota leads to weight gain,obesity,and
HEPATOLOGY,Vol.52,No.5,2010TILG AND MOSCHEN1837
insulin resistance,which suggests that the microbiota and/or microbiota-regulated host factors might i
nflu-ence energy absorption,adiposity,systemic inflamma-tion,and development of insulin resistance.35,36 Endotoxin and Its Role in Obesity.Endotoxin(li-popolysaccharide[LPS]),a key constituent of many bacteria prent in our microbiota,plays a central role in innate immune respons and has been considered the so-called‘‘cond hit’’in previous NASH models.9 Manipulation at the gut surface,including dietary ingredients,may affect LPS metabolism and result in incread circulating plasma levels.It has been demon-strated that intake of a high-fat or a high-carbohydrate diet in humans over only3days leads to an increa in circulating LPS ,‘‘cond hit’’).37 Endotoxemia,however,might not only lead to sys-temic inflammation but might also worn obesity itlf.38When endotoxemia was induced for4weeks in lean mice,liver and adipo tissue weight gain were incread similarly as after a high-fat diet.This weight gain was paralleled by hepatic insulin resistance,and could be prevented by antibiotic therapy.Patients with NAFLD demonstrate incread gut permeability,which importantly has been associated with the verity of liver steatosis but not with the degree of inflammation (NASH).39This study therefore suggests that gut-derived factors/signals such as endotoxin might also affect accumulation of hepatic fat.
Intestinal Epithelium:Linking Nutrients to Meta-bolic Dias.Our microbiota might influence sys-te
mic immune respons.Such an effect might take place via their capacity to digest dietaryfiber resulting in the production of short-chain fatty acids(SCFA). SCFAs have anti-inflammatory functions in various models of colitis and human ulcerative colitis probably via interaction with its receptor,the G protein–coupled receptor43(Gpr43).40Gpr43À/Àmice show systemic inflammation in various tissues,41similar to germ-free wild-type mice devoid of bacterial ferment-ing capacity and hence with almost abnt SCFAs in the gut.Various other ,fasting-induced adipo factor;Gpr41)have been characterized that might interfere with metabolism/adiposity,highlighting how the intestinal microbiota and its products might directly regulate host gene expression and affect sys-temic inflammation.42-45The pathways involve the intestinal epithelium as‘‘nsor’’of the microbiota, implicating a major role for the intestinal epithelium in determining systemic metabolic functions(for details,e Fig.1).Interference with our microbiota via probiotics or prebiotics might therefore be benefi-cial and improve systemic inflammation/metabolic function.So far,only a few animal studies have been performed that suggest that this might indeed be the ca.23,46,47
榛子树儿童打屁股Toll-Like Receptors and Role of Innate Immunity in Obesity-Related Inflammation.Toll-like receptors (TLRs),also expresd on the gut epithelium,can respond to nutritional lipids such as free fatty acids and might thereby have a role in the pathogenesis of obesity-associated inflammation/insulin resista
nce.48 The recognition of fatty acids by TLR4can induce the production of proinflammatory cytokines in macro-phages and epithelial cells.49TLR-4–deficient mice are protected from high-fat diet-induced inflammation and insulin resistance.50It is,however,not universally accepted whether saturated free fatty acids are ligands for certain TLRs becau it has been demonstrated that saturated fatty acids might not directly stimulate TLR-dependent signaling.51Therefore,obrved effects in the above discusd in vivo study49could also be accounted by gut-derived endotoxin or by endotoxin contamination of the lipids employed.
Other TLRs may also be involved in obesity-related inflammation.TLR9promotes steatohepatitis becau TLR9-deficient mice are protected from liver inflam-mation.52The importance of the gut as‘‘metabolic organ’’has been convincingly demonstrated by a recent report indicating that mice deficient in TLR5develop all features of metabolic syndrome including hyperpha-gia,obesity,insulin resistance,pancreatic inflamma-tion,and hepatic steatosis.53TLR5deficiency affected the composition of the gut microbiota and,remark-ably,transfer of the microbiota from TLR5À/Àmice to healthy mice resulted in transfer of dia.There are two major implications of this work:(1)the innate immune system plays a critical role in the development of the metabolic syndrome and(2)transfer of the gut microbiota to wild-type germ-free mice results in v-eral features of de nov
o ,metabolic syn-drome),again supporting a major role for our micro-biota in metabolic inflammation.
Adipo Tissue-Derived Signals:The Adipo Tissue Attacks the Liver
Adipo tissue has appeared in the last decade as a highly active endocrine and immune organ with the capacity of producing various mediators including adi-pocytokines and cytokines both in health and dia. The balance/imbalance of an adipo tissue‘‘mediator cocktail’’may profoundly affect not only the situation in the adipo tissue but especially in important target organs such as the liver(Fig.1).
花生猪脚汤1838TILG AND MOSCHEN HEPATOLOGY,November2010
Adiponectin:Prototypic Adipocytokine in Health and Dia.Adiponectin is an anti-inflammatory adi-pocytokine that signals through two receptors.54-56Obesity is associated with hypoadiponectinemia,and adiponectin levels increa after weight loss.55Adipo-nectin induces extracellular Ca 2þinflux by adiponectin receptor 1,which is necessary for activation of adeno-sine monophosphate–activated protein kina (AMPK)and Sirtuin 1(Sirt1).57Hepatocyte-specific deletion of Sirt1leads not only to hepatic steatosis but also to ER stress and liver inflammation.58Genetically
obe lep-tin-deficient ob/ob mice exhibit a reversal of
the
Fig.1.The multiple parallel hits model.Lipotoxicity:(1)A liver loaded with lipids consisting primarily of trigylcerides might reflect a benign process becau trigylcerides might exert mostly protective effects.Furthermore,hyperleptinemia leads to oxidation of hepatic lipids,thereby also protecting this organ from lipotoxicity.When the capacity of peripheral and central organs of detoxifying ‘‘aggressive lipids’’fails,lipotoxic attack of the liver might begin.Inflammation may precede steatosis in NASH.Gut-derived signals:Many signals beyond endotoxin might affect hepatic steatosis and inflammation.Several pathways have been identified how the gut microbiota might influence host energy metabolism:(2)Abnce of the microbiota in germ-free mice correlates with incread activity of phosphorylated AMPK in the liver and the muscle (not shown).(3)Some of the breakdown products of polysaccharides are metabolized to SCFAs.SCFAs such as propionate and acetate are ligands for the G protein–coupled receptors Gpr41and Gpr43.Shortage of SCFAs might allow the evolution of systemic inflammatory events.Such mechanisms elegantly combine diet,microbiota,and the epithelial cell as ‘‘nutrient nsor.’’(4)The microbiota decreas epithelial expression of fasting-induced adipo-cyte factor (Fiaf ),which functions as a circulating lipoprotein lipa (LPL)inhibitor and therefore is an important regulator of peripheral fat stor-age.(5)Several TLRs,such as TLR5or TLR9,
are not only able to affect microbiota but also to regulate metabolism,systemic inflammation,and insulin resistance,thus highlighting the role of the innate immune system in metabolic inflammation as obrved in NASH.(6)Various nutrients such as trans fatty acids (TFAs),fructo or aryl hydrocarbon receptor (AhR)ligands such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD)may directly lead to steatosis/liver inflammation.Adipo tissue–derived signals:Signals derived from the adipo tissue beyond toxic lipids might play a central role in NAFLD/NASH.(7)Here,adipocytokines such as adiponectin and leptin,certain proinflammatory cytokines such as TNF a or IL-6,and others (the death receptor Fas,PPAR c )are of key relevance.The cytokine/adipocytokine milieu might be critical becau ob/ob -adiponectin tg mice,although becoming verely obe,are not insulin-resistant.This suggests that in the hierarchy of process soluble mediators play the central role.Adipo-derived mediators might indeed affect target organs such as the liver,becau JNK1adipo-deficient mice are protected from diet-induced obesity,and experiments have demonstrated that this effect is mediated mainly by IL-6(a cytokine),which is of key impor-tance in human obesity.
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diabetic phenotype with normalization of gluco and insulin levels upon transgenic overexpression of the full-length isoform of adiponectin,despite retaining the obe phenotype.59This report convinci
ngly dem-onstrates that,despite massive expansion of subcutane-ous adipo tissue,high-level expression of adipo tis-sue adiponectin reduces liver fat content and improves insulin resistance.Therefore,also in humans,a suffi-cient production of adiponectin might play a central role in establishing a balance where local and systemic/ liver inflammation is prevented.60In the hierarchy of process in the adipo tissue,soluble mediators such as adiponectin might be the‘‘big players.’’
Leptin.Becau adipocytes expand with triglycer-ides,leptin cretion increas proportionally.61Hyper-leptinemia reduces fat content in peripheral organs. Becau leptin stimulates fatty acid oxidation,adipo-cytes would be oxidizing,rather than storing fat if the endogenous leptin they synthesize acts on them.62,63 Such an autocrine/paracrine relationship between lep-tin and its creting cell,the adipocyte,is prevented by a progressive decline of adipocyte leptin receptor expression.It is assumed that leptin’s capacity to oxi-dize lipids is fully operative in the liver,thereby mini-mizing ectopic lipid accumulation,at least temporarily. Whether such a mechanism is operative in NAFLD is not known.
IL-6and TNF a:Key(Adipo)cytokines.Expression of IL-6and TNF a,two important proinflammatory cytokines,is profoundly incread in human fat cells from obe subjects and patients with insulin re
sist-ance.64IL-6rum levels are elevated in obe patients and weight loss results in decread IL-6rum lev-els.65,66Enhanced TNF a expression in adipo tissue of obe subjects decreas following weight loss.67 Insulin resistance is an important feature of NAFLD and is caud by a variety of factors,including soluble mediators derived from immune cells and/or adipo tissue.68Insulin resistance may augment inflammation in NASH becau patients with type2diabetes melli-tus are often wor in terms of histopathological changes such as ballooning,apoptosis,and lobular and/or portal inflammation.1Serine phosphorylation of insulin receptor substrate by inflammatory signal transducers such as c-jun N-terminal protein kina1 (JNK1)or inhibitor of nuclear factor-j B kina-b (IKK b)is considered one of the key aspects that dis-rupt insulin signaling.Sabio ported that JNK1 signaling specifically in adipo tissue conquent to a high-fat diet caus hyperinsulinemia,hepatic steatosis, and hepatic insulin resistance.69Importantly,this distal effect of adipo tissue on the liver was mediated via incread JNK1-dependent IL-6cretion from adipo-cytes,proving that adipo tissue–derived IL-6regu-lates distal metabolic effects in the liver.It has to be stated that in this and other models,a high-fat diet is a prerequisite to induce‘‘pathology,’’telling us that indeed‘‘an inflammatory diet’’might exist that drives certain process including liver inflammation at the end.
We recently demonstrated that such a mechanism as suggested by Sabio et al.might also be operative in human obesity.70In this study,IL-6expression has been more than100-fold higher in adipo tissue(sub-cutaneous and visceral)compared to its liver expres-sion,suggesting that in vere obesity,the adipo tis-sue is indeed the major source of IL-6.Weight loss resulted in a dramatic decrea,especially of IL-6and TNF a expression with subquent reduced expression of hepatic suppressor of cytokine signaling3(SOCS3) expression and improved insulin nsitivity,and hence evidence of hepatic conquences of the alterations in adipo tissue.The liver might be a key target organ for adipo tissue–derived IL-6and TNF a,becau continuous IL-6/TNF a exposure affects hepatic insulin ,via up-regulation of SOCS3.71Impor-tantly,enhanced expression of proinflammatory cyto-kines in adipo tissue was obrved,although liver inflammation was still abnt,suggesting that adipo tissue inflammation could precede liver inflamma-tion.70Peroxisome proliferator-activated receptor-gamma(PPAR c),a member of the nuclear receptor family,plays a major role in adipogenesis,atherosclero-sis,inflammation,and gluco metabolism.Adipo tissue–specific deletion of PPAR c results in diminished weight gain despite hyperphagia,diminished rum concentrations of leptin/adiponectin,and insulin resist-ance.72,73Mice with a deficiency of the death receptor Fas specifically in adipocytes are not only protected from adipo tissue inflammation(induced by a high-fat diet)but also from hepatic steatosis and hepatic in-sulin resistance.74
Many human studies suggest that the amount of vis-ceral fat directly correlates with degree of hepatic stea-tosis and inflammation.Hepatic inflammation andfi-brosis correlate with the amount of visceral fat.75 T runk fat has been shown to be a major factor leading to incread rum alanine aminotransfera levels, which might reflect more advanced dia such as NASH.76This large clinical study further supports the important association between adipo tissue and liver dia.Besides certain adipocytokines/immune media-tors,the cellular infiltrate in the adipo tissue is also of major importance becau ablation of adipo幼儿玩教具
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