Similarities and Differences in the Pathogenesis of Alcoholic and Nonalcoholic Steatohepatitis

ABSTRACT

Subpopulations of individuals with alcohol-induced fatty livers and nonalcoholic steatosis develop steatohepatitis. Steatohepatitis is defined histologically: increased numbers of injured and dying hepatocytes distinguish this condition from simple steatosis. The increased hepatocyte death is generally accompanied by hepatic accumulation of inflammatory cells and sometimes increases in myofibroblastic cells, leading to hepatic fibrosis and eventually, cirrhosis. The purpose of this review is to summarize similarities and differences in the pathogenesis of steatohepatitis in alcoholic fatty liver disease and nonalcoholic fatty liver disease.

KEYWORDS

Alcoholic fatty liver disease - nonalcoholic fatty liver disease - pathogenesis - steatohepatitis

REFERENCES

• 1 Lieber C S. Alcoholic liver disease: new insights in pathogenesis lead to new treatments.  J Hepatol. 2000;  32(suppl) 113-128
• 2 Molina P E, McClain C, Valla D et al.. Molecular pathology and clinical aspects of alcohol-induced tissue injury.  Alcohol Clin Exp Res. 2002;  26(1) 120-128
• 3 Matteoni C A, Younossi Z M, Gramlich T, Boparai N, Liu Y C, McCullough A J. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.  Gastroenterology. 1999;  116(6) 1413-1419
• 4 McCullough A J. Pathophysiology of nonalcoholic steatohepatitis.  J Clin Gastroenterol. 2006;  40(suppl 1) S17-S29
• 5 Neuschwander-Tetri B A. Fatty liver and the metabolic syndrome.  Curr Opin Gastroenterol. 2007;  23(2) 193-198
• 6 Feldstein A E, Canbay A, Angulo P et al.. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis.  Gastroenterology. 2003;  125(2) 437-443
• 7 Wieckowska A, Zein N N, Yerian L M, Lopez A R, McCullough A J, Feldstein A E. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease.  Hepatology. 2006;  44(1) 27-33
• 8 Feldstein A E, Papouchado B G, Angulo P, Sanderson S, Adams L, Gores G J. Hepatic stellate cells and fibrosis progression in patients with nonalcoholic fatty liver disease.  Clin Gastroenterol Hepatol. 2005;  3(4) 384-389
• 9 Hubscher S G. Histological assessment of non-alcoholic fatty liver disease.  Histopathology. 2006;  49(5) 450-465
• 10 French S W, Nash J, Shitabata P et al.. Pathology of alcoholic liver disease. VA Cooperative Study Group 119.  Semin Liver Dis. 1993;  13(2) 154-169
• 11 Falck-Ytter Y, Younossi Z M, Marchesini G, McCullough A J. Clinical features and natural history of nonalcoholic steatosis syndromes.  Semin Liver Dis. 2001;  21(1) 17-26
• 12 Richardson M M, Jonsson J R, Powell E E et al.. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction.  Gastroenterology. 2007;  133(1) 80-90
• 13 Bugianesi E. Non-alcoholic steatohepatitis and cancer.  Clin Liver Dis. 2007;  11(1) 191-207 , x–xi
• 14 Day C P, James O F. Steatohepatitis: a tale of two “hits”?.  Gastroenterology. 1998;  114(4) 842-845
• 15 Day C P. Natural history of NAFLD: remarkably benign in the absence of cirrhosis.  Gastroenterology. 2005;  129(1) 375-378
• 16 Adams L A, Lymp J F, St Sauver J et al.. The natural history of nonalcoholic fatty liver disease: a population-based cohort study.  Gastroenterology. 2005;  129(1) 113-121
• 17 Sanyal A J. Mechanisms of disease: pathogenesis of nonalcoholic fatty liver disease.  Nat Clin Pract Gastroenterol Hepatol. 2005;  2(1) 46-53
• 18 Yang S, Koteish A, Lin H et al.. Oval cells compensate for damage and replicative senescence of mature hepatocytes in mice with fatty liver disease.  Hepatology. 2004;  39(2) 403-411
• 19 Roskams T, Yang S Q, Koteish A et al.. Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease.  Am J Pathol. 2003;  163(4) 1301-1311
• 20 Sozio M, Crabb D W. Alcohol and lipid metabolism.  Am J Physiol Endocrinol Metab. 2008;  295(1) E10-E16
• 21 Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD).  Prog Lipid Res. 2009;  48 1-26
• 22 Yamaguchi K, Yang L, McCall S et al.. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis.  Hepatology. 2007;  45(6) 1366-1374
• 23 Klaus S. Adipose tissue as a regulator of energy balance.  Curr Drug Targets. 2004;  5(3) 241-250
• 24 Jou J, Choi S S, Diehl A M. Mechanisms of disease progression in nonalcoholic fatty liver disease.  Semin Liver Dis. 2008;  28(4) 370-379
• 25 Rouach H, Fataccioli V, Gentil M, French S W, Morimoto M, Nordmann R. Effect of chronic ethanol feeding on lipid peroxidation and protein oxidation in relation to liver pathology.  Hepatology. 1997;  25(2) 351-355
• 26 Doege H, Baillie R A, Ortegon A M et al.. Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis.  Gastroenterology. 2006;  130(4) 1245-1258
• 27 Zhou J, Febbraio M, Wada T et al.. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis.  Gastroenterology. 2008;  134(2) 556-567
• 28 Febbraio M, Abumrad N A, Hajjar D P et al.. A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism.  J Biol Chem. 1999;  274(27) 19055-19062
• 29 Newberry E P, Xie Y, Kennedy S et al.. Decreased hepatic triglyceride accumulation and altered fatty acid uptake in mice with deletion of the liver fatty acid-binding protein gene.  J Biol Chem. 2003;  278(51) 51664-51672
• 30 Newberry E P, Xie Y, Kennedy S M, Luo J, Davidson N O. Protection against Western diet-induced obesity and hepatic steatosis in liver fatty acid-binding protein knockout mice.  Hepatology. 2006;  44(5) 1191-1205
• 31 Greco D, Kotronen A, Westerbacka J et al.. Gene expression in human NAFLD.  Am J Physiol Gastrointest Liver Physiol. 2008;  294(5) G1281-G1287
• 32 Arner P. The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones.  Trends Endocrinol Metab. 2003;  14(3) 137-145
• 33 Xu A, Wang Y, Keshaw H, Xu L Y, Lam K S, Cooper G J. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice.  J Clin Invest. 2003;  112(1) 91-100
• 34 Chen G, Liang G, Ou J, Goldstein J L, Brown M S. Central role for liver X receptor in insulin-mediated activation of SREBP-1c transcription and stimulation of fatty acid synthesis in liver.  Proc Natl Acad Sci U S A. 2004;  101(31) 11245-11250
• 35 Peraldi P, Spiegelman B. TNF-alpha and insulin resistance: summary and future prospects.  Mol Cell Biochem. 1998;  182(1–2) 169-175
• 36 Hotamisligil G S. Mechanisms of TNF-alpha-induced insulin resistance.  Exp Clin Endocrinol Diabetes. 1999;  107(2) 119-125
• 37 Ji C, Kaplowitz N. Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice.  Gastroenterology. 2003;  124(5) 1488-1499
• 38 Ji C, Chan C, Kaplowitz N. Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model.  J Hepatol. 2006;  45(5) 717-724
• 39 Esfandiari F, Villanueva J A, Wong D H, French S W, Halsted C H. Chronic ethanol feeding and folate deficiency activate hepatic endoplasmic reticulum stress pathway in micropigs.  Am J Physiol Gastrointest Liver Physiol. 2005;  289(1) G54-G63
• 40 Chen H C, Smith S J, Ladha Z et al.. Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1.  J Clin Invest. 2002;  109(8) 1049-1055
• 41 Raabe M, Veniant M M, Sullivan M A et al.. Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice.  J Clin Invest. 1999;  103(9) 1287-1298
• 42 Ji C, Shinohara M, Kuhlenkamp J, Chan C, Kaplowitz N. Mechanisms of protection by the betaine-homocysteine methyltransferase/betaine system in HepG2 cells and primary mouse hepatocytes.  Hepatology. 2007;  46(5) 1586-1596
• 43 Mylonas C, Kouretas D. Lipid peroxidation and tissue damage.  In Vivo. 1999;  13(3) 295-309
• 44 Jaeschke H, Gores G J, Cederbaum A I, Hinson J A, Pessayre D, Lemasters J J. Mechanisms of hepatotoxicity.  Toxicol Sci. 2002;  65(2) 166-176
• 45 Kaikaus R M, Chan W K, Lysenko N, Ray R, Ortiz de Montellano P R, Bass N M. Induction of peroxisomal fatty acid beta-oxidation and liver fatty acid-binding protein by peroxisome proliferators. Mediation via the cytochrome P-450IVA1 omega-hydroxylase pathway.  J Biol Chem. 1993;  268(13) 9593-9603
• 46 Schonfeld P, Wieckowski M R, Wojtczak L. Long-chain fatty acid-promoted swelling of mitochondria: further evidence for the protonophoric effect of fatty acids in the inner mitochondrial membrane.  FEBS Lett. 2000;  471(1) 108-112
• 47 Tang D G, La E, Kern J, Kehrer J P. Fatty acid oxidation and signaling in apoptosis.  Biol Chem. 2002;  383(3–4) 425-442
• 48 Bocher V, Pineda-Torra I, Fruchart J C, Staels B. PPARs: transcription factors controlling lipid and lipoprotein metabolism.  Ann N Y Acad Sci. 2002;  967 7-18
• 49 Clarke S D, Gasperikova D, Nelson C, Lapillonne A, Heird W C. Fatty acid regulation of gene expression: a genomic explanation for the benefits of the mediterranean diet.  Ann N Y Acad Sci. 2002;  967 283-298
• 50 Li Z, Berk M, McIntyre T M, Gores G J, Feldstein A E. The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity.  Hepatology. 2008;  47(5) 1495-1503
• 51 Schaeffler A, Gross P, Buettner R et al.. Fatty acid-induced induction of toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity.  Immunology. 2009;  126 233-245
• 52 Reddy J K. Nonalcoholic steatosis and steatohepatitis. III. Peroxisomal beta-oxidation, PPAR alpha, and steatohepatitis.  Am J Physiol Gastrointest Liver Physiol. 2001;  281(6) G1333-G1339
• 53 Macdonald G A, Prins J B. Peroxisomal fatty acid metabolism, peroxisomal proliferator-activated receptors and non-alcoholic fatty liver disease.  J Gastroenterol Hepatol. 2004;  19(12) 1335-1337
• 54 Reddy J K, Hashimoto T. Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system.  Annu Rev Nutr. 2001;  21 193-230
• 55 Ip E, Farrell G, Hall P, Robertson G, Leclercq I. Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice.  Hepatology. 2004;  39(5) 1286-1296
• 56 Crabb D W, Galli A, Fischer M, You M. Molecular mechanisms of alcoholic fatty liver: role of peroxisome proliferator-activated receptor alpha.  Alcohol. 2004;  34(1) 35-38
• 57 Nanji A A, Dannenberg A J, Jokelainen K, Bass N M. Alcoholic liver injury in the rat is associated with reduced expression of peroxisome proliferator-alpha (PPARalpha)-regulated genes and is ameliorated by PPARalpha activation.  J Pharmacol Exp Ther. 2004;  310(1) 417-424
• 58 Albano E. Oxidative mechanisms in the pathogenesis of alcoholic liver disease.  Mol Aspects Med. 2008;  29(1–2) 9-16
• 59 Higuchi H, Adachi M, Miura S, Gores G J, Ishii H. The mitochondrial permeability transition contributes to acute ethanol-induced apoptosis in rat hepatocytes.  Hepatology. 2001;  34(2) 320-328
• 60 Hruszkewycz A M, Bergtold D S. Oxygen radicals, lipid peroxidation and DNA damage in mitochondria.  Basic Life Sci. 1988;  49 449-456
• 61 Caldwell S H, Swerdlow R H, Khan E M et al.. Mitochondrial abnormalities in non-alcoholic steatohepatitis.  J Hepatol. 1999;  31(3) 430-434
• 62 Mannaerts G P, Van Veldhoven P P, Casteels M. Peroxisomal lipid degradation via beta- and alpha-oxidation in mammals.  Cell Biochem Biophys. 2000;  32(Spring) 73-87
• 63 Hermesh O, Kalderon B, Bar-Tana J. Mitochondria uncoupling by a long chain fatty acyl analogue.  J Biol Chem. 1998;  273(7) 3937-3942
• 64 Weltman M D, Farrell G C, Hall P, Ingelman-Sundberg M, Liddle C. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis.  Hepatology. 1998;  27(1) 128-133
• 65 Chalasani N, Gorski J C, Asghar M S et al.. Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis.  Hepatology. 2003;  37(3) 544-550
• 66 Leclercq I A, Farrell G C, Field J, Bell D R, Gonzalez F J, Robertson G R. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis.  J Clin Invest. 2000;  105(8) 1067-1075
• 67 Garcia-Ruiz I, Rodriguez-Juan C, Diaz-Sanjuan T et al.. Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice.  Hepatology. 2006;  44(3) 581-591
• 68 Ardies C M, Lasker J M, Lieber C S. Characterization of the cytochrome P-450 monooxygenase system of hamster liver microsomes. Effects of prior treatment with ethanol and other xenobiotics.  Biochem Pharmacol. 1987;  36(21) 3613-3619
• 69 Castillo T, Koop D R, Kamimura S, Triadafilopoulos G, Tsukamoto H. Role of cytochrome P-450 2E1 in ethanol-, carbon tetrachloride- and iron-dependent microsomal lipid peroxidation.  Hepatology. 1992;  16(4) 992-996
• 70 Thiele G M, Freeman T L, Klassen L W. Immunologic mechanisms of alcoholic liver injury.  Semin Liver Dis. 2004;  24(3) 273-287
• 71 Garcia-Ruiz C, Morales A, Ballesta A, Rodes J, Kaplowitz N, Fernandez-Checa J C. Effect of chronic ethanol feeding on glutathione and functional integrity of mitochondria in periportal and perivenous rat hepatocytes.  J Clin Invest. 1994;  94(1) 193-201
• 72 Garcia-Ruiz C, Morales A, Colell A et al.. Feeding S-adenosyl-L-methionine attenuates both ethanol-induced depletion of mitochondrial glutathione and mitochondrial dysfunction in periportal and perivenous rat hepatocytes.  Hepatology. 1995;  21(1) 207-214
• 73 Mato J M, Camara J, Fernandez de Paz J et al.. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial.  J Hepatol. 1999;  30(6) 1081-1089
• 74 Garcia-Ruiz C, Colell A, Morales A, Kaplowitz N, Fernandez-Checa J C. Role of oxidative stress generated from the mitochondrial electron transport chain and mitochondrial glutathione status in loss of mitochondrial function and activation of transcription factor nuclear factor-kappa B: studies with isolated mitochondria and rat hepatocytes.  Mol Pharmacol. 1995;  48(5) 825-834
• 75 Mansouri A, Fromenty B, Berson A et al.. Multiple hepatic mitochondrial DNA deletions suggest premature oxidative aging in alcoholic patients.  J Hepatol. 1997;  27(1) 96-102
• 76 Rolla R, Vay D, Mottaran E et al.. Detection of circulating antibodies against malondialdehyde-acetaldehyde adducts in patients with alcohol-induced liver disease.  Hepatology. 2000;  31(4) 878-884
• 77 Cao Q, Mak K M, Lieber C S. Cytochrome P4502E1 primes macrophages to increase TNF-alpha production in response to lipopolysaccharide.  Am J Physiol Gastrointest Liver Physiol. 2005;  289(1) G95-G107
• 78 Boden G, She P, Mozzoli M et al.. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kappaB pathway in rat liver.  Diabetes. 2005;  54(12) 3458-3465
• 79 Wheeler M D, Kono H, Yin M et al.. The role of Kupffer cell oxidant production in early ethanol-induced liver disease.  Free Radic Biol Med. 2001;  31(12) 1544-1549
• 80 Thakur V, Pritchard M T, McMullen M R, Wang Q, Nagy L E. Chronic ethanol feeding increases activation of NADPH oxidase by lipopolysaccharide in rat Kupffer cells: role of increased reactive oxygen in LPS-stimulated ERK1/2 activation and TNF-alpha production.  J Leukoc Biol. 2006;  79(6) 1348-1356
• 81 Kono H, Rusyn I, Yin M et al.. NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease.  J Clin Invest. 2000;  106(7) 867-872
• 82 Magnusson C, Vaux D L. Signalling by CD95 and TNF receptors: not only life and death.  Immunol Cell Biol. 1999;  77(1) 41-46
• 83 Leist M, Gantner F, Bohlinger I, Germann P G, Tiegs G, Wendel A. Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-alpha requires transcriptional arrest.  J Immunol. 1994;  153(4) 1778-1788
• 84 Barnes P J, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases.  N Engl J Med. 1997;  336(15) 1066-1071
• 85 Friedman S L. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury.  J Biol Chem. 2000;  275(4) 2247-2250
• 86 Brenner D A, O'Hara M, Angel P, Chojkier M, Karin M. Prolonged activation of Jun and collagenase genes by tumour necrosis factor-alpha.  Nature. 1989;  337(6208) 661-663
• 87 Lieber C S, Leo M A, Cao Q et al.. The combination of S-adenosylmethionine and dilinoleoylphosphatidylcholine attenuates non-alcoholic steatohepatitis produced in rats by a high-fat diet.  Nutr Res. 2007;  27(9) 565-573
• 88 Feo F, Pascale R, Garcea R et al.. Effect of the variations of S-adenosyl-L-methionine liver content on fat accumulation and ethanol metabolism in ethanol-intoxicated rats.  Toxicol Appl Pharmacol. 1986;  83(2) 331-341
• 89 Stewart S, Prince M, Bassendine M et al.. A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis.  J Hepatol. 2007;  47(2) 277-283
• 90 Nanji A A, Yang E K, Fogt F, Sadrzadeh S M, Dannenberg A J. Medium chain triglycerides and vitamin E reduce the severity of established experimental alcoholic liver disease.  J Pharmacol Exp Ther. 1996;  277(3) 1694-1700
• 91 Choi S S, Sicklick J K, Ma Q et al.. Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice.  Hepatology. 2006;  44(5) 1267-1277
• 92 Kaufman R J. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls.  Genes Dev. 1999;  13(10) 1211-1233
• 93 Kaufman R J. Orchestrating the unfolded protein response in health and disease.  J Clin Invest. 2002;  110(10) 1389-1398
• 94 Rutkowski D T, Kaufman R J. A trip to the ER: coping with stress.  Trends Cell Biol. 2004;  14(1) 20-28
• 95 Gentile C L, Pagliassotti M J. The role of fatty acids in the development and progression of nonalcoholic fatty liver disease.  J Nutr Biochem. 2008;  19(9) 567-576
• 96 Feng B, Yao P M, Li Y et al.. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages.  Nat Cell Biol. 2003;  5(9) 781-792
• 97 Bird G L, Sheron N, Goka A K, Alexander G J, Williams R S. Increased plasma tumor necrosis factor in severe alcoholic hepatitis.  Ann Intern Med. 1990;  112(12) 917-920
• 98 Tilg H, Diehl A M. Cytokines in alcoholic and nonalcoholic steatohepatitis.  N Engl J Med. 2000;  343(20) 1467-1476
• 99 Iimuro Y, Gallucci R M, Luster M I, Kono H, Thurman R G. Antibodies to tumor necrosis factor alpha attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat.  Hepatology. 1997;  26(6) 1530-1537
• 100 Nanji A A, Khettry U, Sadrzadeh S M. Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease).  Proc Soc Exp Biol Med. 1994;  205(3) 243-247
• 101 Adachi Y, Moore L E, Bradford B U, Gao W, Thurman R G. Antibiotics prevent liver injury in rats following long-term exposure to ethanol.  Gastroenterology. 1995;  108(1) 218-224
• 102 Tilg H, Moschen A R. Adipocytokines: mediators linking adipose tissue, inflammation and immunity.  Nat Rev Immunol. 2006;  6(10) 772-783
• 103 Lancaster Jr J R, Laster S M, Gooding L R. Inhibition of target cell mitochondrial electron transfer by tumor necrosis factor.  FEBS Lett. 1989;  248(1–2) 169-174
• 104 Houstis N, Rosen E D, Lander E S. Reactive oxygen species have a causal role in multiple forms of insulin resistance.  Nature. 2006;  440(7086) 944-948
• 105 Fox-Robichaud A, Kubes P. Molecular mechanisms of tumor necrosis factor alpha-stimulated leukocyte recruitment into the murine hepatic circulation.  Hepatology. 2000;  31(5) 1123-1127
• 106 Boetticher N C, Peine C J, Kwo P et al.. A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis.  Gastroenterology. 2008;  135 1953-1960
• 107 Naveau S, Chollet-Martin S, Dharancy S et al.. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis.  Hepatology. 2004;  39(5) 1390-1397
• 108 Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial.  Gastroenterology. 2000;  119(6) 1637-1648
• 109 Adams L A, Zein C O, Angulo P, Lindor K D. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis.  Am J Gastroenterol. 2004;  99(12) 2365-2368
• 110 Fernandes J L, de Oliveira R T, Mamoni R L et al.. Pentoxifylline reduces pro-inflammatory and increases anti-inflammatory activity in patients with coronary artery disease–a randomized placebo-controlled study.  Atherosclerosis. 2008;  196(1) 434-442
• 111 Houglum K, Buck M, Adir V, Chojkier M. LAP (NF-IL6) transactivates the collagen alpha 1(I) gene from a 5′ regulatory region.  J Clin Invest. 1994;  94(2) 808-814
• 112 Ramond M J, Poynard T, Rueff B et al.. A randomized trial of prednisolone in patients with severe alcoholic hepatitis.  N Engl J Med. 1992;  326(8) 507-512
• 113 Mathurin P, Mendenhall C L, Carithers Jr R L et al.. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH.  J Hepatol. 2002;  36(4) 480-487
• 114 Aithal G P, Thomas J A, Kaye P V et al.. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis.  Gastroenterology. 2008;  135(4) 1176-1184
• 115 Belfort R, Harrison S A, Brown K et al.. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.  N Engl J Med. 2006;  355(22) 2297-2307
• 116 Nakano S, Nagasawa T, Ijiro T et al.. Bezafibrate prevents hepatic stellate cell activation and fibrogenesis in a murine steatohepatitis model, and suppresses fibrogenic response induced by transforming growth factor-beta1 in a cultured stellate cell line.  Hepatol Res. 2008;  38(10) 1026-1039
• 117 Bergheim I, Guo L, Davis M A et al.. Metformin prevents alcohol-induced liver injury in the mouse: Critical role of plasminogen activator inhibitor-1.  Gastroenterology. 2006;  130(7) 2099-2112
• 118 Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis.  Lancet. 2001;  358(9285) 893-894
• 119 Zhou G, Myers R, Li Y et al.. Role of AMP-activated protein kinase in mechanism of metformin action.  J Clin Invest. 2001;  108(8) 1167-1174
• 120 Caligiuri A, Bertolani C, Guerra C T et al.. Adenosine monophosphate-activated protein kinase modulates the activated phenotype of hepatic stellate cells.  Hepatology. 2008;  47(2) 668-676
• 121 Dong J M, Leung T, Manser E, Lim L. cAMP-induced morphological changes are counteracted by the activated RhoA small GTPase and the Rho kinase ROKalpha.  J Biol Chem. 1998;  273(35) 22554-22562
• 122 Lalor P F, Faint J, Aarbodem Y, Hubscher S G, Adams D H. The role of cytokines and chemokines in the development of steatohepatitis.  Semin Liver Dis. 2007;  27(2) 173-193
• 123 Minokoshi Y, Kim Y B, Peroni O D et al.. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase.  Nature. 2002;  415(6869) 339-343
• 124 Guebre-Xabier M, Yang S, Lin H Z, Schwenk R, Krzych U, Diehl A M. Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: potential mechanism for sensitization to liver damage.  Hepatology. 2000;  31(3) 633-640
• 125 Saxena N K, Ikeda K, Rockey D C, Friedman S L, Anania F A. Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice.  Hepatology. 2002;  35(4) 762-771
• 126 Ikejima K, Takei Y, Honda H et al.. Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat.  Gastroenterology. 2002;  122(5) 1399-1410
• 127 Kamada Y, Tamura S, Kiso S et al.. Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin.  Gastroenterology. 2003;  125(6) 1796-1807
• 128 Bjarnason I, Peters T J, Wise R J. The leaky gut of alcoholism: possible route of entry for toxic compounds.  Lancet. 1984;  1(8370) 179-182
• 129 Mathurin P, Deng Q G, Keshavarzian A, Choudhary S, Holmes E W, Tsukamoto H. Exacerbation of alcoholic liver injury by enteral endotoxin in rats.  Hepatology. 2000;  32(5) 1008-1017
• 130 Cani P D, Bibiloni R, Knauf C et al.. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice.  Diabetes. 2008;  57(6) 1470-1481
• 131 Farhadi A, Gundlapalli S, Shaikh M et al.. Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis.  Liver Int. 2008;  28(7) 1026-1033
• 132 Bode C, Kugler V, Bode J C. Endotoxemia in patients with alcoholic and non-alcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess.  J Hepatol. 1987;  4(1) 8-14
• 133 Bhagwandeen B S, Apte M, Manwarring L, Dickeson J. Endotoxin induced hepatic necrosis in rats on an alcohol diet.  J Pathol. 1987;  152(1) 47-53
• 134 Yin M, Bradford B U, Wheeler M D et al.. Reduced early alcohol-induced liver injury in CD14-deficient mice.  J Immunol. 2001;  166(7) 4737-4742
• 135 Uesugi T, Froh M, Arteel G E, Bradford B U, Thurman R G. Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice.  Hepatology. 2001;  34(1) 101-108
• 136 Li Z, Yang S, Lin H et al.. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease.  Hepatology. 2003;  37(2) 343-350
• 137 Pappo I, Bercovier H, Berry E M, Haviv Y, Gallily R, Freund H R. Polymyxin B reduces total parenteral nutrition-associated hepatic steatosis by its antibacterial activity and by blocking deleterious effects of lipopolysaccharide.  JPEN J Parenter Enteral Nutr. 1992;  16(6) 529-532
• 138 Turnbaugh P J, Ley R E, Mahowald M A, Magrini V, Mardis E R, Gordon J I. An obesity-associated gut microbiome with increased capacity for energy harvest.  Nature. 2006;  444(7122) 1027-1031
• 139 Hritz I, Mandrekar P, Velayudham A et al.. The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88.  Hepatology. 2008;  48(4) 1224-1231
• 140 Liu S, Gallo D J, Green A M et al.. Role of toll-like receptors in changes in gene expression and NF-kappa B activation in mouse hepatocytes stimulated with lipopolysaccharide.  Infect Immun. 2002;  70(7) 3433-3442
• 141 Paik Y H, Schwabe R F, Bataller R, Russo M P, Jobin C, Brenner D A. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells.  Hepatology. 2003;  37(5) 1043-1055
• 142 Cope K, Risby T, Diehl A M. Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis.  Gastroenterology. 2000;  119(5) 1340-1347
• 143 Nair S, Cope K, Risby T H, Diehl A M. Obesity and female gender increase breath ethanol concentration: potential implications for the pathogenesis of nonalcoholic steatohepatitis.  Am J Gastroenterol. 2001;  96(4) 1200-1204
• 144 Svegliati-Baroni G, Inagaki Y, Rincon-Sanchez A R et al.. Early response of alpha2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-beta independent.  Hepatology. 2005;  42(2) 343-352
• 145 Potter J J, Rennie-Tankersley L, Mezey E. Leptin deficiency prevents the activation of the murine alpha 2(I) collagen promoter by acetaldehyde.  Arch Biochem Biophys. 2004;  426(1) 73-77
• 146 Szczepiorkowski Z M, Dickersin G R, Laposata M. Fatty acid ethyl esters decrease human hepatoblastoma cell proliferation and protein synthesis.  Gastroenterology. 1995;  108(2) 515-522