UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Pathogenesis of nonalcoholic fatty liver disease

Author
David A Tendler, MD
Section Editor
Keith D Lindor, MD
Deputy Editor
Anne C Travis, MD, MSc, FACG, AGAF

INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) is a clinico-histopathological entity with histological features that resemble alcohol-induced liver injury, but by definition, it occurs in patients with little or no history of alcohol consumption. It encompasses a histological spectrum that ranges from fat accumulation in hepatocytes without concomitant inflammation or fibrosis (simple hepatic steatosis) to hepatic steatosis with a necroinflammatory component (steatohepatitis) that may or may not have associated fibrosis. The latter condition, referred to as nonalcoholic steatohepatitis (NASH), may progress to cirrhosis in up to 20 percent of patients [1]. NASH is now recognized to be a leading cause of cryptogenic cirrhosis [2].

The pathogenesis of nonalcoholic fatty liver disease has not been fully elucidated. The most widely supported theory implicates insulin resistance as the key mechanism leading to hepatic steatosis, and perhaps also to steatohepatitis. Others have proposed that a "second hit," or additional oxidative injury, is required to manifest the necroinflammatory component of steatohepatitis. Hepatic iron, leptin, antioxidant deficiencies, and intestinal bacteria have all been suggested as potential oxidative stressors.

This topic review will focus on the pathogenesis of NAFLD. An approach to such patients is presented separately. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults" and "Natural history and management of nonalcoholic fatty liver disease in adults".)

CAUSES OF TRIGLYCERIDE ACCUMULATION

Hepatic steatosis is a manifestation of excessive triglyceride accumulation in the liver. This can occur from the excessive importation of free fatty acids (FFA) from adipose tissue, from diminished hepatic export of FFA (secondary to reduced synthesis or secretion of very low-density lipoprotein [VLDL]), or from impaired beta-oxidation of FFA. The major sources of triglycerides are from fatty acids stored in adipose tissue and fatty acids newly made within the liver through de novo lipogenesis [3].

Excessive importation of FFA can result from either increased delivery of triglycerides to the liver (as seen with obesity and rapid weight loss), or from excessive conversion of carbohydrates and proteins to triglycerides (eg, secondary to overfeeding or use of total parenteral nutrition).

           

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Wed Mar 09 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 116:1413.
  2. Caldwell SH, Oelsner DH, Iezzoni JC, et al. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999; 29:664.
  3. Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005; 115:1343.
  4. Musso G, Gambino R, De Michieli F, et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 2003; 37:909.
  5. Lettéron P, Sutton A, Mansouri A, et al. Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice. Hepatology 2003; 38:133.
  6. Huang J, Iqbal J, Saha PK, et al. Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver. Hepatology 2007; 46:147.
  7. Fujita K, Nozaki Y, Wada K, et al. Dysfunctional very-low-density lipoprotein synthesis and release is a key factor in nonalcoholic steatohepatitis pathogenesis. Hepatology 2009; 50:772.
  8. Kajikawa S, Harada T, Kawashima A, et al. Highly purified eicosapentaenoic acid ethyl ester prevents development of steatosis and hepatic fibrosis in rats. Dig Dis Sci 2010; 55:631.
  9. Corey KE, Vuppalanchi R, Wilson LA, et al. NASH resolution is associated with improvements in HDL and triglyceride levels but not improvement in LDL or non-HDL-C levels. Aliment Pharmacol Ther 2015; 41:301.
  10. Ip E, Farrell GC, Robertson G, et al. Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice. Hepatology 2003; 38:123.
  11. Cortez-Pinto H, Chatham J, Chacko VP, et al. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 1999; 282:1659.
  12. Xu A, Wang Y, Keshaw H, et al. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 2003; 112:91.
  13. Gary-Bobo M, Elachouri G, Gallas JF, et al. Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology 2007; 46:122.
  14. Villanueva CJ, Monetti M, Shih M, et al. Specific role for acyl CoA:Diacylglycerol acyltransferase 1 (Dgat1) in hepatic steatosis due to exogenous fatty acids. Hepatology 2009; 50:434.
  15. Bala S, Marcos M, Szabo G. Emerging role of microRNAs in liver diseases. World J Gastroenterol 2009; 15:5633.
  16. Hand NJ, Master ZR, Le Lay J, Friedman JR. Hepatic function is preserved in the absence of mature microRNAs. Hepatology 2009; 49:618.
  17. Jin X, Ye YF, Chen SH, et al. MicroRNA expression pattern in different stages of nonalcoholic fatty liver disease. Dig Liver Dis 2009; 41:289.
  18. Sheth SG, Gordon FD, Chopra S. Nonalcoholic steatohepatitis. Ann Intern Med 1997; 126:137.
  19. Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001; 120:1183.
  20. Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002; 35:373.
  21. Willner IR, Waters B, Patil SR, et al. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol 2001; 96:2957.
  22. Pagano G, Pacini G, Musso G, et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology 2002; 35:367.
  23. Marchesini G, Brizi M, Morselli-Labate AM, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999; 107:450.
  24. Hamaguchi M, Kojima T, Takeda N, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005; 143:722.
  25. Marchesini G, Brizi M, Bianchi G, et al. Metformin in non-alcoholic steatohepatitis. Lancet 2001; 358:893.
  26. Marchesini G, Pagotto U, Bugianesi E, et al. Low ghrelin concentrations in nonalcoholic fatty liver disease are related to insulin resistance. J Clin Endocrinol Metab 2003; 88:5674.
  27. Kim HJ, Kim HJ, Lee KE, et al. Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch Intern Med 2004; 164:2169.
  28. Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med 2010; 362:1082.
  29. Carulli L, Canedi I, Rondinella S, et al. Genetic polymorphisms in non-alcoholic fatty liver disease: interleukin-6-174G/C polymorphism is associated with non-alcoholic steatohepatitis. Dig Liver Dis 2009; 41:823.
  30. Rotman Y, Koh C, Zmuda JM, et al. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 2010; 52:894.
  31. Sookoian S, Rosselli MS, Gemma C, et al. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter. Hepatology 2010; 52:1992.
  32. Domenici FA, Brochado MJ, Martinelli Ade L, et al. Peroxisome proliferator-activated receptors alpha and gamma2 polymorphisms in nonalcoholic fatty liver disease: a study in Brazilian patients. Gene 2013; 529:326.
  33. Lin YC, Chang PF, Chang MH, Ni YH. A common variant in the peroxisome proliferator-activated receptor-γ coactivator-1α gene is associated with nonalcoholic fatty liver disease in obese children. Am J Clin Nutr 2013; 97:326.
  34. Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology 2016; 150:1147.
  35. Gastaldelli A, Cusi K, Pettiti M, et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology 2007; 133:496.
  36. van der Poorten D, Milner KL, Hui J, et al. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology 2008; 48:449.
  37. Wieckowska A, Papouchado BG, Li Z, et al. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol 2008; 103:1372.
  38. Calvert VS, Collantes R, Elariny H, et al. A systems biology approach to the pathogenesis of obesity-related nonalcoholic fatty liver disease using reverse phase protein microarrays for multiplexed cell signaling analysis. Hepatology 2007; 46:166.
  39. Fiorentino L, Vivanti A, Cavalera M, et al. Increased tumor necrosis factor alpha-converting enzyme activity induces insulin resistance and hepatosteatosis in mice. Hepatology 2010; 51:103.
  40. Ryan MW, Harrison SA, Neuschwander-Tetri BA. Serum amyloid A and C-reactive protein diminish after treatment of NASH with rosiglitazone (abstract). Gastroenterology 2003; 124A.
  41. Gastaldelli A, Harrison SA, Belfort-Aguilar R, et al. Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology 2009; 50:1087.
  42. Facchini FS, Hua NW, Stoohs RA. Effect of iron depletion in carbohydrate-intolerant patients with clinical evidence of nonalcoholic fatty liver disease. Gastroenterology 2002; 122:931.
  43. Kelley DE, McKolanis TM, Hegazi RA, et al. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab 2003; 285:E906.
  44. Kral JG, Lundholm K, Björntorp P, et al. Hepatic lipid metabolism in severe human obesity. Metabolism 1977; 26:1025.
  45. Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA. Effect of fatty acids on glucose production and utilization in man. J Clin Invest 1983; 72:1737.
  46. Porez G, Prawitt J, Gross B, Staels B. Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease. J Lipid Res 2012; 53:1723.
  47. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385:956.
  48. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346:1221.
  49. Sreekumar R, Rosado B, Rasmussen D, Charlton M. Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis. Hepatology 2003; 38:244.
  50. Hruszkewycz AM. Evidence for mitochondrial DNA damage by lipid peroxidation. Biochem Biophys Res Commun 1988; 153:191.
  51. Chen J, Schenker S, Frosto TA, Henderson GI. Inhibition of cytochrome c oxidase activity by 4-hydroxynonenal (HNE). Role of HNE adduct formation with the enzyme subunits. Biochim Biophys Acta 1998; 1380:336.
  52. Rensen SS, Slaats Y, Driessen A, et al. Activation of the complement system in human nonalcoholic fatty liver disease. Hepatology 2009; 50:1809.
  53. Rensen SS, Slaats Y, Nijhuis J, et al. Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis. Am J Pathol 2009; 175:1473.
  54. Tajiri K, Shimizu Y, Tsuneyama K, Sugiyama T. Role of liver-infiltrating CD3+CD56+ natural killer T cells in the pathogenesis of nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2009; 21:673.
  55. Yang JD, Abdelmalek MF, Pang H, et al. Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology 2014; 59:1406.
  56. Guy CD, Suzuki A, Zdanowicz M, et al. Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology 2012; 55:1711.
  57. Swiderska-Syn M, Suzuki A, Guy CD, et al. Hedgehog pathway and pediatric nonalcoholic fatty liver disease. Hepatology 2013; 57:1814.
  58. Machado MV, Michelotti GA, Pereira Tde A, et al. Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis. Gut 2015; 64:1148.
  59. Machado MV, Michelotti GA, Jewell ML, et al. Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease. Cell Death Dis 2016; 7:e2096.
  60. Sastre J, Pallardó FV, Llopis J, et al. Glutathione depletion by hyperphagia-induced obesity. Life Sci 1989; 45:183.
  61. Strauss RS, Barlow SE, Dietz WH. Prevalence of abnormal serum aminotransferase values in overweight and obese adolescents. J Pediatr 2000; 136:727.
  62. Baskol G, Baskol M, Kocer D. Oxidative stress and antioxidant defenses in serum of patients with non-alcoholic steatohepatitis. Clin Biochem 2007; 40:776.
  63. Yu J, Chu ES, Wang R, et al. Heme oxygenase-1 protects against steatohepatitis in both cultured hepatocytes and mice. Gastroenterology 2010; 138:694.
  64. Ikura Y, Ohsawa M, Suekane T, et al. Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease: impact on disease progression. Hepatology 2006; 43:506.
  65. Nocito A, Dahm F, Jochum W, et al. Serotonin mediates oxidative stress and mitochondrial toxicity in a murine model of nonalcoholic steatohepatitis. Gastroenterology 2007; 133:608.
  66. Lavine JE. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr 2000; 136:734.
  67. Harrison SA, Torgerson S, Hayashi P, et al. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2003; 98:2485.
  68. Ma X, Hua J, Mohamood AR, et al. A high-fat diet and regulatory T cells influence susceptibility to endotoxin-induced liver injury. Hepatology 2007; 46:1519.
  69. Mendler MH, Turlin B, Moirand R, et al. Insulin resistance-associated hepatic iron overload. Gastroenterology 1999; 117:1155.
  70. Viganò M, Vergani A, Trombini P, et al. Insulin resistance influence iron metabolism and hepatic steatosis in type II diabetes. Gastroenterology 2000; 118:986.
  71. Bonkovsky HL, Jawaid Q, Tortorelli K, et al. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis. J Hepatol 1999; 31:421.
  72. Solanas-Barca M, Mateo-Gallego R, Calmarza P, et al. Mutations in HFE causing hemochromatosis are associated with primary hypertriglyceridemia. J Clin Endocrinol Metab 2009; 94:4391.
  73. Valenti L, Fracanzani AL, Bugianesi E, et al. HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology 2010; 138:905.
  74. George DK, Goldwurm S, MacDonald GA, et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998; 114:311.
  75. Nelson JE, Wilson L, Brunt EM, et al. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology 2011; 53:448.
  76. Woods JR Jr, Plessinger MA, Fantel A. An introduction to reactive oxygen species and their possible roles in substance abuse. Obstet Gynecol Clin North Am 1998; 25:219.
  77. Chitturi S, Weltman M, Farrell GC, et al. HFE mutations, hepatic iron, and fibrosis: ethnic-specific association of NASH with C282Y but not with fibrotic severity. Hepatology 2002; 36:142.
  78. Younossi ZM, Gramlich T, Bacon BR, et al. Hepatic iron and nonalcoholic fatty liver disease. Hepatology 1999; 30:847.
  79. Adams LA, Crawford DH, Stuart K, et al. The impact of phlebotomy in nonalcoholic fatty liver disease: A prospective, randomized, controlled trial. Hepatology 2015; 61:1555.
  80. Cohen B, Novick D, Rubinstein M. Modulation of insulin activities by leptin. Science 1996; 274:1185.
  81. Crespo J, Rivero M, Fábrega E, et al. Plasma leptin and TNF-alpha levels in chronic hepatitis C patients and their relationship to hepatic fibrosis. Dig Dis Sci 2002; 47:1604.
  82. Asilmaz E, Cohen P, Miyazaki M, et al. Site and mechanism of leptin action in a rodent form of congenital lipodystrophy. J Clin Invest 2004; 113:414.
  83. Angulo P, Alba LM, Petrovic LM, et al. Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease. J Hepatol 2004; 41:943.
  84. Savvidou S. Low serum adiponectin levels are predictive of advanced hepatic fibrosis in patients with NAFLD. J Clin Gastroenterology 2009; 43:765.
  85. Musso G, Gambino R, Durazzo M, et al. Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology 2005; 42:1175.
  86. Gastaldelli A, Harrison S, Belfort-Aguiar R, et al. Pioglitazone in the treatment of NASH: the role of adiponectin. Aliment Pharmacol Ther 2010; 32:769.
  87. Leclercq IA, Lebrun VA, Stärkel P, Horsmans YJ. Intrahepatic insulin resistance in a murine model of steatohepatitis: effect of PPARgamma agonist pioglitazone. Lab Invest 2007; 87:56.
  88. Satoh H, Nguyen MT, Miles PD, et al. Adenovirus-mediated chronic "hyper-resistinemia" leads to in vivo insulin resistance in normal rats. J Clin Invest 2004; 114:224.
  89. Muse ED, Obici S, Bhanot S, et al. Role of resistin in diet-induced hepatic insulin resistance. J Clin Invest 2004; 114:232.
  90. Wigg AJ, Roberts-Thomson IC, Dymock RB, et al. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001; 48:206.
  91. Miele L, Valenza V, La Torre G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 2009; 49:1877.
  92. Boursier J, Mueller O, Barret M, et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 2016; 63:764.
  93. Cope K, Risby T, Diehl AM. Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology 2000; 119:1340.
  94. Salaspuro M. Bacteriocolonic pathway for ethanol oxidation: characteristics and implications. Ann Med 1996; 28:195.
  95. Mezey E, Imbembo AL, Potter JJ, et al. Endogenous ethanol production and hepatic disease following jejunoileal bypass for morbid obesity. Am J Clin Nutr 1975; 28:1277.
  96. Baraona E, Julkunen R, Tannenbaum L, Lieber CS. Role of intestinal bacterial overgrowth in ethanol production and metabolism in rats. Gastroenterology 1986; 90:103.
  97. Kaji H, Asanuma Y, Yahara O, et al. Intragastrointestinal alcohol fermentation syndrome: report of two cases and review of the literature. J Forensic Sci Soc 1984; 24:461.
  98. Nair S, Cope K, Risby TH, Diehl AM. Obesity and female gender increase breath ethanol concentration: potential implications for the pathogenesis of nonalcoholic steatohepatitis. Am J Gastroenterol 2001; 96:1200.
  99. Pappo I, Bercovier H, Berry E, et al. Antitumor necrosis factor antibodies reduce hepatic steatosis during total parenteral nutrition and bowel rest in the rat. JPEN J Parenter Enteral Nutr 1995; 19:80.
  100. Kirsch R, Clarkson V, Verdonk RC, et al. Rodent nutritional model of steatohepatitis: effects of endotoxin (lipopolysaccharide) and tumor necrosis factor alpha deficiency. J Gastroenterol Hepatol 2006; 21:174.
  101. Brun P, Castagliuolo I, Di Leo V, et al. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2007; 292:G518.
  102. Jin X, Yu CH, Lv GC, Li YM. Increased intestinal permeability in pathogenesis and progress of nonalcoholic steatohepatitis in rats. World J Gastroenterol 2007; 13:1732.
  103. Enomoto N, Yamashina S, Kono H, et al. Development of a new, simple rat model of early alcohol-induced liver injury based on sensitization of Kupffer cells. Hepatology 1999; 29:1680.
  104. Pappo I, Bercovier H, Berry EM, et al. 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; 16:529.
  105. Pappo I, Becovier H, Berry EM, Freund HR. Polymyxin B reduces cecal flora, TNF production and hepatic steatosis during total parenteral nutrition in the rat. J Surg Res 1991; 51:106.
  106. Drenick EJ, Fisler J, Johnson D. Hepatic steatosis after intestinal bypass--prevention and reversal by metronidazole, irrespective of protein-calorie malnutrition. Gastroenterology 1982; 82:535.
  107. Li Z, Yang S, Lin H, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 2003; 37:343.
  108. Zamora-Valdés D, Méndez-Sánchez N. Experimental evidence of obstructive sleep apnea syndrome as a second hit accomplice in nonalcoholic steatohepatitis pathogenesis. Ann Hepatol 2007; 6:281.
  109. Aron-Wisnewsky J, Minville C, Tordjman J, et al. Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese. J Hepatol 2012; 56:225.
  110. Benotti P, Wood GC, Argyropoulos G, et al. The impact of obstructive sleep apnea on nonalcoholic fatty liver disease in patients with severe obesity. Obesity (Silver Spring) 2016; 24:871.
  111. Wouters K, van Gorp PJ, Bieghs V, et al. Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis. Hepatology 2008; 48:474.
  112. Yamazaki Y, Kakizaki S, Horiguchi N, et al. The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic steatohepatitis. Gut 2007; 56:565.
  113. Richardson MM, Jonsson JR, Powell EE, et al. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology 2007; 133:80.