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Pathogenesis of nonalcoholic steatohepatitis

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Abstract

Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease and a risk factor for cirrhosis and hepatocellular carcinoma. The pathological features of NASH include steatosis, hepatocyte injury, inflammation, and various degrees of fibrosis. Steatosis reflects disordered lipid metabolism. Insulin resistance and excessive fatty acid influx to the liver are two important contributing factors. Steatosis is also likely associated with lipotoxicity and cellular stresses such as oxidative stress and endoplasmic reticulum stress, which result in hepatocyte injury. Inflammation and fibrosis are frequently triggered by various signals such as proinflammatory cytokines and chemokines, released by injuried hepatocytes and activated Kupffer cells. Although much progress has been made, the pathogenesis of NASH is not fully elucidated. The purpose of this review is to discuss the current understanding of NASH pathogenesis, mainly focusing on factors contributing to steatosis, hepatocyte injury, inflammation, and fibrosis.

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Abbreviations

ChREBP:

Carbohydrate response element binding protein

CVD:

Cardiovascular disease

DAG:

Diacylglycerol

DAMPs:

Damage-associated molecular patterns

DNL:

De novo lipogenesis

ER:

Endoplasmic reticulum

ETC:

Electron transport chain

FFAs:

Free fatty acids

HCC:

Hepatocellular carcinoma

HH:

Hedgehog

HPCs:

Hepatic progenitor cells

HSC:

Hepatic stellate cell

IR:

Insulin resistance

LPS:

Lipopolysaccharide

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

NLRs:

NOD like receptors

PAMPs:

Pathogen-associated molecular patterns

PNPLA3:

Patatin-like phospholipase domain-containing 3

PPARs:

Peroxisome proliferator-activated receptors

PRR:

Pattern recognition receptors

PUFA:

Polyunsaturated fatty acids

ROS:

Reactive oxygen species

SCFAs:

Short-chain fatty acids

SNP:

Single nucleotide polymorphism

SREBP-1c:

Sterol regulatory element-binding protein 1c

TGF-β:

Transforming growth factor β

TGs:

Triglycerides

TLRs:

Toll like receptors

VEGF:

Vascular endothelial growth factor

VLDL:

Very low density lipoprotein

References

  1. Yoon HJ, Cha BS (2014) Pathogenesis and therapeutic approaches for non-alcoholic fatty liver disease. World J Hepatol 6:800–811

    Article  PubMed  PubMed Central  Google Scholar 

  2. Levene AP, Goldin RD (2012) The epidemiology, pathogenesis and histopathology of fatty liver disease. Histopathology 61:141–152

    Article  PubMed  Google Scholar 

  3. Ahmed M (2015) Non-alcoholic fatty liver disease in 2015. World J Hepatol 7:1450–1459

    Article  PubMed  PubMed Central  Google Scholar 

  4. Dowman JK, Tomlinson JW, Newsome PN (2010) Pathogenesis of non-alcoholic fatty liver disease. QJM 103:71–83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Milic S, Stimac D (2012) Nonalcoholic fatty liver disease/steatohepatitis: epidemiology, pathogenesis, clinical presentation and treatment. Dig Dis 30:158–162

    Article  PubMed  Google Scholar 

  6. Bettermann K, Hohensee T, Haybaeck J (2014) Steatosis and steatohepatitis: complex disorders. Int J Mol Sci 15:9924–9944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA (2011) Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140:124–131

    Article  PubMed  Google Scholar 

  8. Amarapurkar D, Kamani P, Patel N, Gupte P, Kumar P, Agal S, Baijal R, Lala S, Chaudhary D, Deshpande A (2007) Prevalence of non-alcoholic fatty liver disease: population based study. Ann Hepatol 6:161–163

    PubMed  Google Scholar 

  9. Tiniakos DG, Vos MB, Brunt EM (2010) Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol 5:145–171

    Article  CAS  PubMed  Google Scholar 

  10. Younossi ZM (2008) Review article: current management of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Aliment Pharmacol Ther 28:2–12

    Article  CAS  PubMed  Google Scholar 

  11. Bhala N, Jouness RI, Bugianesi E (2013) Epidemiology and natural history of patients with NAFLD. Curr Pharm Des 19:5169–5176

    Article  CAS  PubMed  Google Scholar 

  12. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ (2012) The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 55:2005–2023

    Article  PubMed  Google Scholar 

  13. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH (2009) Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol 51:371–379

    Article  CAS  PubMed  Google Scholar 

  14. Starley BQ, Calcagno CJ, Harrison SA (2010) Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 51:1820–1832

    Article  PubMed  Google Scholar 

  15. Than NN, Newsome PN (2015) A concise review of non-alcoholic fatty liver disease. Atherosclerosis 239:192–202

    Article  CAS  PubMed  Google Scholar 

  16. Angulo P (2010) Long-term mortality in nonalcoholic fatty liver disease: is liver histology of any prognostic significance? Hepatology 51:373–375

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, Kechagias S (2006) Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44:865–873

    Article  CAS  PubMed  Google Scholar 

  18. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P (2005) The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129:113–121

    Article  PubMed  Google Scholar 

  19. Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS (2002) NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 36:1349–1354

    Article  PubMed  Google Scholar 

  20. Ludwig J, Viggiano TR, McGill DB, Oh BJ (1980) Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 55:434–438

    CAS  PubMed  Google Scholar 

  21. Day CP, James OF (1998) Steatohepatitis: a tale of two “hits”? Gastroenterology 114:842–845

    Article  CAS  PubMed  Google Scholar 

  22. Cusi K (2012) Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 142(711–725):e716

    Google Scholar 

  23. Neuschwander-Tetri BA (2010) Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 52:774–788

    Article  PubMed  CAS  Google Scholar 

  24. Neuschwander-Tetri BA (2010) Nontriglyceride hepatic lipotoxicity: the new paradigm for the pathogenesis of NASH. Curr Gastroenterol Rep 12:49–56

    Article  PubMed  Google Scholar 

  25. Tilg H, Moschen AR (2010) Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52:1836–1846

    Article  CAS  PubMed  Google Scholar 

  26. Yilmaz Y (2012) Review article: is non-alcoholic fatty liver disease a spectrum, or are steatosis and non-alcoholic steatohepatitis distinct conditions? Aliment Pharmacol Ther 36:815–823

    Article  CAS  PubMed  Google Scholar 

  27. Adams LA, Ratziu V (2015) Non-alcoholic fatty liver—perhaps not so benign. J Hepatol 62:1002–1004

    Article  PubMed  Google Scholar 

  28. McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM (2015) Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol 62:1148–1155

    Article  PubMed  Google Scholar 

  29. Basaranoglu M, Kayacetin S, Yilmaz N, Kayacetin E, Tarcin O, Sonsuz A (2010) Understanding mechanisms of the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 16:2223–2226

    Article  PubMed  PubMed Central  Google Scholar 

  30. Machado M, Marques-Vidal P, Cortez-Pinto H (2006) Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol 45:600–606

    Article  PubMed  Google Scholar 

  31. Angulo P (2002) Nonalcoholic fatty liver disease. N Engl J Med 346:1221–1231

    Article  CAS  PubMed  Google Scholar 

  32. Byrne CD, Targher G (2015) NAFLD: a multisystem disease. J Hepatol 62:S47–S64

    Article  PubMed  Google Scholar 

  33. Anstee QM, Targher G, Day CP (2013) Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 10:330–344

    Article  CAS  PubMed  Google Scholar 

  34. Armstrong MJ, Adams LA, Canbay A, Syn WK (2014) Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology 59:1174–1197

    Article  CAS  PubMed  Google Scholar 

  35. Lim S, Oh TJ, Koh KK (2015) Mechanistic link between nonalcoholic fatty liver disease and cardiometabolic disorders. Int J Cardiol 201:408–414

    Article  PubMed  Google Scholar 

  36. Oni ET, Agatston AS, Blaha MJ, Fialkow J, Cury R, Sposito A, Erbel R, Blankstein R, Feldman T, Al-Mallah MH, Santos RD, Budoff MJ, Nasir K (2013) A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care? Atherosclerosis 230:258–267

    Article  CAS  PubMed  Google Scholar 

  37. Hassan K, Bhalla V, Ezz El Regal M, A-Kader HH (2014) Nonalcoholic fatty liver disease: a comprehensive review of a growing epidemic. World J Gastroenterol 20:12082–12101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ong JP, Pitts A, Younossi ZM (2008) Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J Hepatol 49:608–612

    Article  PubMed  Google Scholar 

  39. Iroz A, Couty JP, Postic C (2015) Hepatokines: unlocking the multi-organ network in metabolic diseases. Diabetologia 58:1699–1703

    Article  CAS  PubMed  Google Scholar 

  40. Stefan N, Haring HU (2013) The role of hepatokines in metabolism. Nat Rev Endocrinol 9:144–152

    Article  CAS  PubMed  Google Scholar 

  41. Yoo HJ, Choi KM (2015) Hepatokines as a link between obesity and cardiovascular diseases. Diabetes Metab J 39:10–15

    Article  PubMed  PubMed Central  Google Scholar 

  42. Yilmaz Y, Yonal O, Kurt R, Ari F, Oral AY, Celikel CA, Korkmaz S, Ulukaya E, Ozdogan O, Imeryuz N, Avsar E, Kalayci C (2010) Serum fetuin A/alpha2HS-glycoprotein levels in patients with non-alcoholic fatty liver disease: relation with liver fibrosis. Ann Clin Biochem 47:549–553

    Article  PubMed  CAS  Google Scholar 

  43. Lebensztejn DM, Bialokoz-Kalinowska I, Klusek-Oksiuta M, Tarasow E, Wojtkowska M, Kaczmarski M (2014) Serum fetuin A concentration is elevated in children with non-alcoholic fatty liver disease. Adv Med Sci 59:81–84

    Article  PubMed  Google Scholar 

  44. Yilmaz Y, Eren F, Yonal O, Kurt R, Aktas B, Celikel CA, Ozdogan O, Imeryuz N, Kalayci C, Avsar E (2010) Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease. Eur J Clin Invest 40:887–892

    Article  CAS  PubMed  Google Scholar 

  45. Li H, Fang Q, Gao F, Fan J, Zhou J, Wang X, Zhang H, Pan X, Bao Y, Xiang K, Xu A, Jia W (2010) Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. J Hepatol 53:934–940

    Article  CAS  PubMed  Google Scholar 

  46. Dushay J, Chui PC, Gopalakrishnan GS, Varela-Rey M, Crawley M, Fisher FM, Badman MK, Martinez-Chantar ML, Maratos-Flier E (2010) Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology 139:456–463

    Article  CAS  PubMed  Google Scholar 

  47. Choi HY, Hwang SY, Lee CH, Hong HC, Yang SJ, Yoo HJ, Seo JA, Kim SG, Kim NH, Baik SH, Choi DS, Choi KM (2013) Increased selenoprotein p levels in subjects with visceral obesity and nonalcoholic Fatty liver disease. Diabetes Metab J 37:63–71

    Article  PubMed  PubMed Central  Google Scholar 

  48. Yang SJ, Hwang SY, Choi HY, Yoo HJ, Seo JA, Kim SG, Kim NH, Baik SH, Choi DS, Choi KM (2011) Serum selenoprotein P levels in patients with type 2 diabetes and prediabetes: implications for insulin resistance, inflammation, and atherosclerosis. J Clin Endocrinol Metab 96:E1325–E1329

    Article  CAS  PubMed  Google Scholar 

  49. Chow WS, Xu A, Woo YC, Tso AW, Cheung SC, Fong CH, Tse HF, Chau MT, Cheung BM, Lam KS (2013) Serum fibroblast growth factor-21 levels are associated with carotid atherosclerosis independent of established cardiovascular risk factors. Arterioscler Thromb Vasc Biol 33:2454–2459

    Article  CAS  PubMed  Google Scholar 

  50. Shen Y, Ma X, Zhou J, Pan X, Hao Y, Zhou M, Lu Z, Gao M, Bao Y, Jia W (2013) Additive relationship between serum fibroblast growth factor 21 level and coronary artery disease. Cardiovasc Diabetol 12:124

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Weikert C, Stefan N, Schulze MB, Pischon T, Berger K, Joost HG, Haring HU, Boeing H, Fritsche A (2008) Plasma fetuin-a levels and the risk of myocardial infarction and ischemic stroke. Circulation 118:2555–2562

    Article  CAS  PubMed  Google Scholar 

  52. Dogru T, Genc H, Tapan S, Aslan F, Ercin CN, Ors F, Kara M, Sertoglu E, Karslioglu Y, Bagci S, Kurt I, Sonmez A (2013) Plasma fetuin-A is associated with endothelial dysfunction and subclinical atherosclerosis in subjects with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf) 78:712–717

    Article  CAS  Google Scholar 

  53. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ (2005) Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 115:1343–1351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cohen JC, Horton JD, Hobbs HH (2011) Human fatty liver disease: old questions and new insights. Science 332:1519–1523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bradbury MW (2006) Lipid metabolism and liver inflammation. I. Hepatic fatty acid uptake: possible role in steatosis. Am J Physiol Gastrointest Liver Physiol 290:G194–G198

    Article  CAS  PubMed  Google Scholar 

  56. Musso G, Gambino R, Cassader M (2009) Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res 48:1–26

    Article  CAS  PubMed  Google Scholar 

  57. Fabbrini E, Magkos F (2015) Hepatic steatosis as a marker of metabolic dysfunction. Nutrients 7:4995–5019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hudgins LC, Hellerstein MK, Seidman CE, Neese RA, Tremaroli JD, Hirsch J (2000) Relationship between carbohydrate-induced hypertriglyceridemia and fatty acid synthesis in lean and obese subjects. J Lipid Res 41:595–604

    CAS  PubMed  Google Scholar 

  59. Parks EJ (2002) Dietary carbohydrate’s effects on lipogenesis and the relationship of lipogenesis to blood insulin and glucose concentrations. Br J Nutr 87(Suppl 2):S247–S253

    Article  CAS  PubMed  Google Scholar 

  60. Diraison F, Beylot M (1998) Role of human liver lipogenesis and reesterification in triglycerides secretion and in FFA reesterification. Am J Physiol 274:E321–E327

    CAS  PubMed  Google Scholar 

  61. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN (2001) Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120:1183–1192

    Article  CAS  PubMed  Google Scholar 

  62. Miele L, Grieco A, Armuzzi A, Candelli M, Forgione A, Gasbarrini A, Gasbarrini G (2003) Hepatic mitochondrial beta-oxidation in patients with nonalcoholic steatohepatitis assessed by 13C-octanoate breath test. Am J Gastroenterol 98:2335–2336

    Article  PubMed  Google Scholar 

  63. Marra F, Gastaldelli A, Svegliati Baroni G, Tell G, Tiribelli C (2008) Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis. Trends Mol Med 14:72–81

    Article  CAS  PubMed  Google Scholar 

  64. Reddy JK (2001) Nonalcoholic steatosis and steatohepatitis. III. Peroxisomal beta-oxidation, PPAR alpha, and steatohepatitis. Am J Physiol Gastrointest Liver Physiol 281:G1333–G1339

    CAS  PubMed  Google Scholar 

  65. Day CP (2002) Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol 16:663–678

    Article  CAS  PubMed  Google Scholar 

  66. Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S (2008) Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 134:424–431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Adiels M, Taskinen MR, Packard C, Caslake MJ, Soro-Paavonen A, Westerbacka J, Vehkavaara S, Hakkinen A, Olofsson SO, Yki-Jarvinen H, Boren J (2006) Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia 49:755–765

    Article  CAS  PubMed  Google Scholar 

  68. Musso G, Gambino R, Durazzo M, Biroli G, Carello M, Faga E, Pacini G, De Michieli F, Rabbione L, Premoli A, Cassader M, Pagano G (2005) Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology 42:1175–1183

    Article  CAS  PubMed  Google Scholar 

  69. Zhu L, Baker SS, Liu W, Tao MH, Patel R, Nowak NJ, Baker RD (2011) Lipid in the livers of adolescents with nonalcoholic steatohepatitis: combined effects of pathways on steatosis. Metabolism 60:1001–1011

    Article  CAS  PubMed  Google Scholar 

  70. Fujita K, Nozaki Y, Wada K, Yoneda M, Fujimoto Y, Fujitake M, Endo H, Takahashi H, Inamori M, Kobayashi N, Kirikoshi H, Kubota K, Saito S, Nakajima A (2009) Dysfunctional very-low-density lipoprotein synthesis and release is a key factor in nonalcoholic steatohepatitis pathogenesis. Hepatology 50:772–780

    Article  CAS  PubMed  Google Scholar 

  71. Brown MS, Goldstein JL (2008) Selective versus total insulin resistance: a pathogenic paradox. Cell Metab 7:95–96

    Article  CAS  PubMed  Google Scholar 

  72. Bugianesi E, Gastaldelli A, Vanni E, Gambino R, Cassader M, Baldi S, Ponti V, Pagano G, Ferrannini E, Rizzetto M (2005) Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 48:634–642

    Article  CAS  PubMed  Google Scholar 

  73. Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, Okunade A, Klein S (2009) Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci USA 106:15430–15435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Korenblat KM, Fabbrini E, Mohammed BS, Klein S (2008) Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology 134:1369–1375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, Goto T, Westerbacka J, Sovijarvi A, Halavaara J, Yki-Jarvinen H (2002) Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 87:3023–3028

    Article  CAS  PubMed  Google Scholar 

  76. Finck BN, Hall AM (2015) Does diacylglycerol accumulation in fatty liver disease cause hepatic insulin resistance? Biomed Res Int 2015:104132

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Birkenfeld AL, Shulman GI (2014) Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology 59:713–723

    Article  PubMed  PubMed Central  Google Scholar 

  78. Loria P, Lonardo A, Anania F (2013) Liver and diabetes. A vicious circle. Hepatol Res 43:51–64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Perry RJ, Samuel VT, Petersen KF, Shulman GI (2014) The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510:84–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Takamura T, Misu H, Ota T, Kaneko S (2012) Fatty liver as a consequence and cause of insulin resistance: lessons from type 2 diabetic liver. Endocr J 59:745–763

    Article  CAS  PubMed  Google Scholar 

  81. Williams KH, Shackel NA, Gorrell MD, McLennan SV, Twigg SM (2013) Diabetes and nonalcoholic fatty liver disease: a pathogenic duo. Endocr Rev 34:84–129

    Article  CAS  PubMed  Google Scholar 

  82. Tanoli T, Yue P, Yablonskiy D, Schonfeld G (2004) Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity. J Lipid Res 45:941–947

    Article  CAS  PubMed  Google Scholar 

  83. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ (2009) Autophagy regulates lipid metabolism. Nature 458:1131–1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Yang L, Li P, Fu S, Calay ES, Hotamisligil GS (2010) Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab 11:467–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chen R, Wang Q, Song S, Liu F, He B, Gao X (2016) Protective role of autophagy in methionine–choline deficient diet-induced advanced nonalcoholic steatohepatitis in mice. Eur J Pharmacol 770:126–133

    Article  CAS  PubMed  Google Scholar 

  86. Kashima J, Shintani-Ishida K, Nakajima M, Maeda H, Unuma K, Uchiyama Y, Yoshida K (2014) Immunohistochemical study of the autophagy marker microtubule-associated protein 1 light chain 3 in normal and steatotic human livers. Hepatol Res 44:779–787

    Article  CAS  PubMed  Google Scholar 

  87. Fukuo Y, Yamashina S, Sonoue H, Arakawa A, Nakadera E, Aoyama T, Uchiyama A, Kon K, Ikejima K, Watanabe S (2014) Abnormality of autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease. Hepatol Res 44:1026–1036

    Article  CAS  PubMed  Google Scholar 

  88. Liu HY, Han J, Cao SY, Hong T, Zhuo D, Shi J, Liu Z, Cao W (2009) Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin. J Biol Chem 284:31484–31492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ferre P, Foufelle F (2010) Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes Metab 12(Suppl 2):83–92

    Article  CAS  PubMed  Google Scholar 

  90. Lim JW, Dillon J, Miller M (2014) Proteomic and genomic studies of non-alcoholic fatty liver disease—clues in the pathogenesis. World J Gastroenterol 20:8325–8340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Rodriguez-Suarez E, Duce AM, Caballeria J, Martinez Arrieta F, Fernandez E, Gomara C, Alkorta N, Ariz U, Martinez-Chantar ML, Lu SC, Elortza F, Mato JM (2010) Non-alcoholic fatty liver disease proteomics. Proteomics Clin Appl 4:362–371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. DiPilato LM, Ahmad F, Harms M, Seale P, Manganiello V, Birnbaum MJ (2015) The role of PDE3B phosphorylation in the inhibition of lipolysis by insulin. Mol Cell Biol 35:2752–2760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Chakrabarti P, Kim JY, Singh M, Shin YK, Kim J, Kumbrink J, Wu Y, Lee MJ, Kirsch KH, Fried SK, Kandror KV (2013) Insulin inhibits lipolysis in adipocytes via the evolutionarily conserved mTORC1-Egr1-ATGL-mediated pathway. Mol Cell Biol 33:3659–3666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chakrabarti P, English T, Shi J, Smas CM, Kandror KV (2010) Mammalian target of rapamycin complex 1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storage. Diabetes 59:775–781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chakrabarti P, Kandror KV (2011) Adipose triglyceride lipase: a new target in the regulation of lipolysis by insulin. Curr Diabetes Rev 7:270–277

    Article  CAS  PubMed  Google Scholar 

  96. Tinahones FJ, Garrido-Sanchez L, Miranda M, Garcia-Almeida JM, Macias-Gonzalez M, Ceperuelo V, Gluckmann E, Rivas-Marin J, Vendrell J, Garcia-Fuentes E (2010) Obesity and insulin resistance-related changes in the expression of lipogenic and lipolytic genes in morbidly obese subjects. Obes Surg 20:1559–1567

    Article  CAS  PubMed  Google Scholar 

  97. Larter CZ, Chitturi S, Heydet D, Farrell GC (2010) A fresh look at NASH pathogenesis. Part 1: the metabolic movers. J Gastroenterol Hepatol 25:672–690

    Article  CAS  PubMed  Google Scholar 

  98. Matherly SC, Puri P (2012) Mechanisms of simple hepatic steatosis: not so simple after all. Clin Liver Dis 16:505–524

    Article  PubMed  Google Scholar 

  99. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A (2002) Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570–578

    Article  CAS  PubMed  Google Scholar 

  100. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI (2004) The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 101:15718–15723

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Ferolla SM, Armiliato GN, Couto CA, Ferrari TC (2014) The role of intestinal bacteria overgrowth in obesity-related nonalcoholic fatty liver disease. Nutrients 6:5583–5599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Duwaerts CC, Maher JJ (2014) Mechanisms of liver injury in non-alcoholic steatohepatitis. Curr Hepatol Rep 13:119–129

    Article  PubMed  PubMed Central  Google Scholar 

  103. Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA, Bewtra M, Knights D, Walters WA, Knight R, Sinha R, Gilroy E, Gupta K, Baldassano R, Nessel L, Li H, Bushman FD, Lewis JD (2011) Linking long-term dietary patterns with gut microbial enterotypes. Science 334:105–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhu L, Baker RD, Baker SS (2015) Gut microbiome and nonalcoholic fatty liver diseases. Pediatr Res 77:245–251

    Article  CAS  PubMed  Google Scholar 

  105. Zhu L, Baker SS, Gill C, Liu W, Alkhouri R, Baker RD, Gill SR (2013) Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57:601–609

    Article  CAS  PubMed  Google Scholar 

  106. Jiang C, Xie C, Li F, Zhang L, Nichols RG, Krausz KW, Cai J, Qi Y, Fang ZZ, Takahashi S, Tanaka N, Desai D, Amin SG, Albert I, Patterson AD, Gonzalez FJ (2015) Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 125:386–402

    Article  PubMed  PubMed Central  Google Scholar 

  107. Duncan SH, Louis P, Thomson JM, Flint HJ (2009) The role of pH in determining the species composition of the human colonic microbiota. Environ Microbiol 11:2112–2122

    Article  PubMed  Google Scholar 

  108. Wostmann BS, Larkin C, Moriarty A, Bruckner-Kardoss E (1983) Dietary intake, energy metabolism, and excretory losses of adult male germfree Wistar rats. Lab Anim Sci 33:46–50

    CAS  PubMed  Google Scholar 

  109. Schwiertz A, Taras D, Schafer K, Beijer S, Bos NA, Donus C, Hardt PD (2010) Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring) 18:190–195

    Article  Google Scholar 

  110. Cho I, Yamanishi S, Cox L, Methe BA, Zavadil J, Li K, Gao Z, Mahana D, Raju K, Teitler I, Li H, Alekseyenko AV, Blaser MJ (2012) Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 488:621–626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Moschen AR, Kaser S, Tilg H (2013) Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends Endocrinol Metab 24:537–545

    Article  CAS  PubMed  Google Scholar 

  112. den Besten G, Havinga R, Bleeker A, Rao S, Gerding A, van Eunen K, Groen AK, Reijngoud DJ, Bakker BM (2014) The short-chain fatty acid uptake fluxes by mice on a guar gum supplemented diet associate with amelioration of major biomarkers of the metabolic syndrome. PLoS One 9:e107392

    Article  CAS  Google Scholar 

  113. den Besten G, Gerding A, van Dijk TH, Ciapaite J, Bleeker A, van Eunen K, Havinga R, Groen AK, Reijngoud DJ, Bakker BM (2015) Protection against the metabolic syndrome by guar gum-derived short-chain fatty acids depends on peroxisome proliferator-activated receptor gamma and glucagon-like peptide-1. PLoS One 10:e0136364

    Article  CAS  Google Scholar 

  114. den Besten G, Bleeker A, Gerding A, van Eunen K, Havinga R, van Dijk TH, Oosterveer MH, Jonker JW, Groen AK, Reijngoud DJ, Bakker BM (2015) Short-chain fatty acids protect against high-fat diet-induced obesity via a PPARgamma-dependent switch from lipogenesis to fat oxidation. Diabetes 64:2398–2408

    Article  CAS  Google Scholar 

  115. Blomstrand R (1971) Observations of the formation of ethanol in the intestinal tract in man. Life Sci II 10:575–582

    Article  CAS  PubMed  Google Scholar 

  116. Dawes EA, Foster SM (1956) The formation of ethanol in Escherichia coli. Biochim Biophys Acta 22:253–265

    Article  CAS  PubMed  Google Scholar 

  117. Volynets V, Kuper MA, Strahl S, Maier IB, Spruss A, Wagnerberger S, Konigsrainer A, Bischoff SC, Bergheim I (2012) Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD). Dig Dis Sci 57:1932–1941

    Article  CAS  PubMed  Google Scholar 

  118. Paege LM, Gibbs M (1961) Anaerobic dissimilation of glucose-C14 by Escherichia coli. J Bacteriol 81:107–110

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Clark DP (1989) The fermentation pathways of Escherichia coli. FEMS Microbiol Rev 5:223–234

    CAS  PubMed  Google Scholar 

  120. Brooks JB, Basta MT, el Kholy AM (1985) Studies of metabolites in diarrheal stool specimens containing Shigella species by frequency-pulsed electron capture gas-liquid chromatography. J Clin Microbiol 21:599–606

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Loomba R, Schork N, Chen CH, Bettencourt R, Bhatt A, Ang B, Nguyen P, Hernandez C, Richards L, Salotti J, Lin S, Seki E, Nelson KE, Sirlin CB, Brenner D (2015) Heritability of hepatic fibrosis and steatosis based on a prospective twin study. Gastroenterology 149:1784–1793

    Article  PubMed  Google Scholar 

  122. Krawczyk M, Bonfrate L, Portincasa P (2010) Nonalcoholic fatty liver disease. Best Pract Res Clin Gastroenterol 24:695–708

    Article  CAS  PubMed  Google Scholar 

  123. Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, Gudnason V, Eiriksdottir G, Garcia ME, Launer LJ, Nalls MA, Clark JM, Mitchell BD, Shuldiner AR, Butler JL, Tomas M, Hoffmann U, Hwang SJ, Massaro JM, O’Donnell CJ, Sahani DV, Salomaa V, Schadt EE, Schwartz SM, Siscovick DS, Voight BF, Carr JJ, Feitosa MF, Harris TB, Fox CS, Smith AV, Kao WH, Hirschhorn JN, Borecki IB (2011) Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 7:e1001324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Dongiovanni P, Romeo S, Valenti L (2015) Genetic factors in the pathogenesis of nonalcoholic fatty liver and steatohepatitis. Biomed Res Int 2015:460190

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH (2008) Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 40:1461–1465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Musso G, Gambino R, Cassader M (2010) Non-alcoholic fatty liver disease from pathogenesis to management: an update. Obes Rev 11:430–445

    Article  CAS  PubMed  Google Scholar 

  127. Basantani MK, Sitnick MT, Cai L, Brenner DS, Gardner NP, Li JZ, Schoiswohl G, Yang K, Kumari M, Gross RW, Zechner R, Kershaw EE (2011) Pnpla3/adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. J Lipid Res 52:318–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Qiao A, Liang J, Ke Y, Li C, Cui Y, Shen L, Zhang H, Cui A, Liu X, Liu C, Chen Y, Zhu Y, Guan Y, Fang F, Chang Y (2011) Mouse patatin-like phospholipase domain-containing 3 influences systemic lipid and glucose homeostasis. Hepatology 54:509–521

    Article  CAS  PubMed  Google Scholar 

  129. Goffredo M, Caprio S, Feldstein AE, D’Adamo E, Shaw MM, Pierpont B, Savoye M, Zhao H, Bale AE, Santoro N (2015) Role of the TM6SF2 rs58542926 in the pathogenesis of non-alcoholic pediatric fatty liver disease (NAFLD): a multiethnic study. Hepatology 63(1):117–125. doi:10.1002/hep.28283

    Article  PubMed  CAS  Google Scholar 

  130. Anstee QM, Day CP (2015) The genetics of nonalcoholic fatty liver disease: spotlight on PNPLA3 and TM6SF2. Semin Liver Dis 35:270–290

    Article  CAS  PubMed  Google Scholar 

  131. Anstee QM, Day CP (2013) The genetics of NAFLD. Nat Rev Gastroenterol Hepatol 10:645–655

    Article  CAS  PubMed  Google Scholar 

  132. Cheung O, Sanyal AJ (2010) Recent advances in nonalcoholic fatty liver disease. Curr Opin Gastroenterol 26:202–208

    Article  PubMed  Google Scholar 

  133. Zambo V, Simon-Szabo L, Szelenyi P, Kereszturi E, Banhegyi G, Csala M (2013) Lipotoxicity in the liver. World J Hepatol 5:550–557

    PubMed  PubMed Central  Google Scholar 

  134. Alkhouri N, Dixon LJ, Feldstein AE (2009) Lipotoxicity in nonalcoholic fatty liver disease: not all lipids are created equal. Expert Rev Gastroenterol Hepatol 3:445–451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Listenberger LL, Han X, Lewis SE, Cases S, Farese RV Jr, Ory DS, Schaffer JE (2003) Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci USA 100:3077–3082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Listenberger LL, Ory DS, Schaffer JE (2001) Palmitate-induced apoptosis can occur through a ceramide-independent pathway. J Biol Chem 276:14890–14895

    Article  CAS  PubMed  Google Scholar 

  137. Liu W, Baker SS, Baker RD, Zhu L (2015) Antioxidant mechanisms in nonalcoholic fatty liver disease. Curr Drug Targets 16:1301–1314

    Article  CAS  PubMed  Google Scholar 

  138. Desai S, Baker SS, Liu W, Moya DA, Browne RW, Mastrandrea L, Baker RD, Zhu L (2014) Paraoxonase 1 and oxidative stress in paediatric non-alcoholic steatohepatitis. Liver Int 34:110–117

    Article  CAS  PubMed  Google Scholar 

  139. Liu W, Baker SS, Baker RD, Nowak NJ, Zhu L (2011) Upregulation of hemoglobin expression by oxidative stress in hepatocytes and its implication in nonalcoholic steatohepatitis. PLoS One 6:e24363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Baker SS, Baker RD, Liu W, Nowak NJ, Zhu L (2010) Role of alcohol metabolism in non-alcoholic steatohepatitis. PLoS One 5:e9570

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Moya D, Baker SS, Liu W, Garrick M, Kozielski R, Baker RD, Zhu L (2014) Novel pathway for iron deficiency in pediatric non-alcoholic steatohepatitis. Clin Nutr 34(3):549–556. doi:10.1016/j.clnu.2014.06.011

    Article  PubMed  CAS  Google Scholar 

  142. Paradies G, Paradies V, Ruggiero FM, Petrosillo G (2014) Oxidative stress, cardiolipin and mitochondrial dysfunction in nonalcoholic fatty liver disease. World J Gastroenterol 20:14205–14218

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Takaki A, Kawai D, Yamamoto K (2014) Molecular mechanisms and new treatment strategies for non-alcoholic steatohepatitis (NASH). Int J Mol Sci 15:7352–7379

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Rolo AP, Teodoro JS, Palmeira CM (2012) Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic Biol Med 52:59–69

    Article  CAS  PubMed  Google Scholar 

  145. Brandt ML, Harmon CM, Helmrath MA, Inge TH, McKay SV, Michalsky MP (2010) Morbid obesity in pediatric diabetes mellitus: surgical options and outcomes. Nat Rev Endocrinol 6:637–645

    Article  PubMed  Google Scholar 

  146. Zhang XQ, Xu CF, Yu CH, Chen WX, Li YM (2014) Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 20:1768–1776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Passos E, Ascensao A, Martins MJ, Magalhaes J (2015) Endoplasmic reticulum stress response in non-alcoholic steatohepatitis: the possible role of physical exercise. Metabolism 64:780–792

    Article  CAS  PubMed  Google Scholar 

  148. Ashraf NU, Sheikh TA (2015) Endoplasmic reticulum stress and oxidative stress in the pathogenesis of non-alcoholic fatty liver disease. Free Radic Res 49:1405–1418

    Article  CAS  PubMed  Google Scholar 

  149. Brunt EM (2011) Non-alcoholic fatty liver disease: what’s new under the microscope? Gut 60:1152–1158

    Article  PubMed  Google Scholar 

  150. Yeh MM, Brunt EM (2014) Pathological features of fatty liver disease. Gastroenterology 147:754–764

    Article  CAS  PubMed  Google Scholar 

  151. Lackner C, Gogg-Kamerer M, Zatloukal K, Stumptner C, Brunt EM, Denk H (2008) Ballooned hepatocytes in steatohepatitis: the value of keratin immunohistochemistry for diagnosis. J Hepatol 48:821–828

    Article  CAS  PubMed  Google Scholar 

  152. Kang JH (2013) Modification and inactivation of Cu, Zn-superoxide dismutase by the lipid peroxidation product, acrolein. BMB Rep 46:555–560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Pigeolet E, Corbisier P, Houbion A, Lambert D, Michiels C, Raes M, Zachary MD, Remacle J (1990) Glutathione peroxidase, superoxide dismutase, and catalase inactivation by peroxides and oxygen derived free radicals. Mech Ageing Dev 51:283–297

    Article  CAS  PubMed  Google Scholar 

  154. Pessayre D, Mansouri A, Fromenty B (2002) Nonalcoholic steatosis and steatohepatitis. V. Mitochondrial dysfunction in steatohepatitis. Am J Physiol Gastrointest Liver Physiol 282:G193–G199

    Article  CAS  PubMed  Google Scholar 

  155. Haque M, Sanyal AJ (2002) The metabolic abnormalities associated with non-alcoholic fatty liver disease. Best Pract Res Clin Gastroenterol 16:709–731

    Article  CAS  PubMed  Google Scholar 

  156. Koek GH, Liedorp PR, Bast A (2011) The role of oxidative stress in non-alcoholic steatohepatitis. Clin Chim Acta 412:1297–1305

    Article  CAS  PubMed  Google Scholar 

  157. Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A, Diehl AM (1999) Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 282:1659–1664

    Article  CAS  PubMed  Google Scholar 

  158. Perez-Carreras M, Del Hoyo P, Martin MA, Rubio JC, Martin A, Castellano G, Colina F, Arenas J, Solis-Herruzo JA (2003) Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology 38:999–1007

    Article  CAS  PubMed  Google Scholar 

  159. Caldwell SH, Swerdlow RH, Khan EM, Iezzoni JC, Hespenheide EE, Parks JK, Parker WD Jr (1999) Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepatol 31:430–434

    Article  CAS  PubMed  Google Scholar 

  160. Seki S, Kitada T, Yamada T, Sakaguchi H, Nakatani K, Wakasa K (2002) In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases. J Hepatol 37:56–62

    Article  CAS  PubMed  Google Scholar 

  161. Peverill W, Powell LW, Skoien R (2014) Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int J Mol Sci 15:8591–8638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, Gores GJ (2003) Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125:437–443

    Article  PubMed  Google Scholar 

  163. Liu K, Lou J, Wen T, Yin J, Xu B, Ding W, Wang A, Liu D, Zhang C, Chen D, Li N (2013) Depending on the stage of hepatosteatosis, p53 causes apoptosis primarily through either DRAM-induced autophagy or BAX. Liver Int 33:1566–1574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Farrell GC, Larter CZ, Hou JY, Zhang RH, Yeh MM, Williams J, dela Pena A, Francisco R, Osvath SR, Brooling J, Teoh N, Sedger LM (2009) Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression. J Gastroenterol Hepatol 24:443–452

    Article  CAS  PubMed  Google Scholar 

  165. Yahagi N, Shimano H, Matsuzaka T, Sekiya M, Najima Y, Okazaki S, Okazaki H, Tamura Y, Iizuka Y, Inoue N, Nakagawa Y, Takeuchi Y, Ohashi K, Harada K, Gotoda T, Nagai R, Kadowaki T, Ishibashi S, Osuga J, Yamada N (2004) p53 involvement in the pathogenesis of fatty liver disease. J Biol Chem 279:20571–20575

    Article  CAS  PubMed  Google Scholar 

  166. Panasiuk A, Dzieciol J, Panasiuk B, Prokopowicz D (2006) Expression of p53, Bax and Bcl-2 proteins in hepatocytes in non-alcoholic fatty liver disease. World J Gastroenterol 12:6198–6202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Lebeaupin C, Proics E, de Bieville CH, Rousseau D, Bonnafous S, Patouraux S, Adam G, Lavallard VJ, Rovere C, Le Thuc O, Saint-Paul MC, Anty R, Schneck AS, Iannelli A, Gugenheim J, Tran A, Gual P, Bailly-Maitre B (2015) ER stress induces NLRP3 inflammasome activation and hepatocyte death. Cell Death Dis 6:e1879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Bechmann LP, Gieseler RK, Sowa JP, Kahraman A, Erhard J, Wedemeyer I, Emons B, Jochum C, Feldkamp T, Gerken G, Canbay A (2010) Apoptosis is associated with CD36/fatty acid translocase upregulation in non-alcoholic steatohepatitis. Liver Int 30:850–859

    Article  CAS  PubMed  Google Scholar 

  169. Feldstein AE, Canbay A, Guicciardi ME, Higuchi H, Bronk SF, Gores GJ (2003) Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice. J Hepatol 39:978–983

    Article  CAS  PubMed  Google Scholar 

  170. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Cawthorn WP, Sethi JK (2008) TNF-alpha and adipocyte biology. FEBS Lett 582:117–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Wenfeng Z, Yakun W, Di M, Jianping G, Chuanxin W, Chun H (2014) Kupffer cells: increasingly significant role in nonalcoholic fatty liver disease. Ann Hepatol 13:489–495

    PubMed  Google Scholar 

  173. Baffy G (2009) Kupffer cells in non-alcoholic fatty liver disease: the emerging view. J Hepatol 51:212–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Marra F, Lotersztajn S (2013) Pathophysiology of NASH: perspectives for a targeted treatment. Curr Pharm Des 19:5250–5269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Wan J, Benkdane M, Teixeira-Clerc F, Bonnafous S, Louvet A, Lafdil F, Pecker F, Tran A, Gual P, Mallat A, Lotersztajn S, Pavoine C (2014) M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology 59:130–142

    Article  CAS  PubMed  Google Scholar 

  176. Smith K (2013) Liver disease: Kupffer cells regulate the progression of ALD and NAFLD. Nat Rev Gastroenterol Hepatol 10:503

    Article  PubMed  Google Scholar 

  177. Harmon RC, Tiniakos DG, Argo CK (2011) Inflammation in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol 5:189–200

    Article  PubMed  Google Scholar 

  178. Hubscher SG (2006) Histological assessment of non-alcoholic fatty liver disease. Histopathology 49:450–465

    Article  CAS  PubMed  Google Scholar 

  179. Rensen SS, Slaats Y, Nijhuis J, Jans A, Bieghs V, Driessen A, Malle E, Greve JW, Buurman WA (2009) Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis. Am J Pathol 175:1473–1482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Nijhuis J, Rensen SS, Slaats Y, van Dielen FM, Buurman WA, Greve JW (2009) Neutrophil activation in morbid obesity, chronic activation of acute inflammation. Obesity (Silver Spring) 17:2014–2018

    Article  CAS  Google Scholar 

  181. Liang W, Lindeman JH, Menke AL, Koonen DP, Morrison M, Havekes LM, van den Hoek AM, Kleemann R (2014) Metabolically induced liver inflammation leads to NASH and differs from LPS- or IL-1beta-induced chronic inflammation. Lab Invest 94:491–502

    Article  CAS  PubMed  Google Scholar 

  182. Sutter AG, Palanisamy AP, Lench JH, Jessmore AP, Chavin KD (2015) Development of steatohepatitis in Ob/Ob mice is dependent on Toll-like receptor 4. Ann Hepatol 14:735–743

    PubMed  Google Scholar 

  183. Kapil S, Duseja A, Sharma BK, Singla B, Chakraborti A, Das A, Ray P, Dhiman RK, Chawla Y (2015) Small intestinal bacterial overgrowth and toll like receptor signaling in patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol 31(1): 213–21. doi:10.1111/jgh.13058

    Article  CAS  Google Scholar 

  184. Yuan J, Baker SS, Liu W, Alkhouri R, Baker RD, Xie J, Ji G, Zhu L (2014) Endotoxemia unrequired in the pathogenesis of pediatric nonalcoholic steatohepatitis. J Gastroenterol Hepatol 29:1292–1298

    Article  CAS  PubMed  Google Scholar 

  185. Pal D, Dasgupta S, Kundu R, Maitra S, Das G, Mukhopadhyay S, Ray S, Majumdar SS, Bhattacharya S (2012) Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med 18:1279–1285

    Article  CAS  PubMed  Google Scholar 

  186. Erridge C, Samani NJ (2009) Saturated fatty acids do not directly stimulate Toll-like receptor signaling. Arterioscler Thromb Vasc Biol 29:1944–1949

    Article  CAS  PubMed  Google Scholar 

  187. Tse E, Helbig KJ, Van der Hoek K, McCartney EM, Van der Hoek M, George J, Beard MR (2015) Fatty acids induce a pro-inflammatory gene expression profile in Huh-7 cells that attenuates the anti-HCV action of interferon. J Interferon Cytokine Res 35:392–400

    Article  CAS  PubMed  Google Scholar 

  188. Miura K, Yang L, van Rooijen N, Brenner DA, Ohnishi H, Seki E (2013) Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology 57:577–589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Duarte N, Coelho IC, Patarrao RS, Almeida JI, Penha-Goncalves C, Macedo MP (2015) How inflammation impinges on NAFLD: a role for Kupffer cells. Biomed Res Int 2015:984578

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Kwanten WJ, Martinet W, Michielsen PP, Francque SM (2014) Role of autophagy in the pathophysiology of nonalcoholic fatty liver disease: a controversial issue. World J Gastroenterol 20:7325–7338

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Macaluso FS, Maida M, Petta S (2015) Genetic background in nonalcoholic fatty liver disease: a comprehensive review. World J Gastroenterol 21:11088–11111

    Article  PubMed  PubMed Central  Google Scholar 

  192. Schattenberg JM, Schuppan D (2011) Nonalcoholic steatohepatitis: the therapeutic challenge of a global epidemic. Curr Opin Lipidol 22:479–488

    Article  CAS  PubMed  Google Scholar 

  193. Puche JE, Saiman Y, Friedman SL (2013) Hepatic stellate cells and liver fibrosis. Compr Physiol 3:1473–1492

    Article  PubMed  Google Scholar 

  194. Iwaisako K, Brenner DA, Kisseleva T (2012) What’s new in liver fibrosis? The origin of myofibroblasts in liver fibrosis. J Gastroenterol Hepatol 27(Suppl 2):65–68

    Article  CAS  PubMed  Google Scholar 

  195. Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115:209–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Friedman SL (2008) Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88:125–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Nobili V, Carpino G, Alisi A, Franchitto A, Alpini G, De Vito R, Onori P, Alvaro D, Gaudio E (2012) Hepatic progenitor cells activation, fibrosis, and adipokines production in pediatric nonalcoholic fatty liver disease. Hepatology 56:2142–2153

    Article  CAS  PubMed  Google Scholar 

  198. Fausto N (2004) Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 39:1477–1487

    Article  PubMed  Google Scholar 

  199. Machado MV, Michelotti GA, Pereira TA, Xie G, Premont R, Cortez-Pinto H, Diehl AM (2015) Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease. J Hepatol 63:962–970

    Article  CAS  PubMed  Google Scholar 

  200. Espanol-Suner R, Carpentier R, Van Hul N, Legry V, Achouri Y, Cordi S, Jacquemin P, Lemaigre F, Leclercq IA (2012) Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice. Gastroenterology 143(1564–1575):e1567

    Google Scholar 

  201. Gouw AS, Clouston AD, Theise ND (2011) Ductular reactions in human liver: diversity at the interface. Hepatology 54:1853–1863

    Article  PubMed  Google Scholar 

  202. Dooley S, ten Dijke P (2012) TGF-beta in progression of liver disease. Cell Tissue Res 347:245–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Weng HL, Ciuclan L, Liu Y, Hamzavi J, Godoy P, Gaitantzi H, Kanzler S, Heuchel R, Ueberham U, Gebhardt R, Breitkopf K, Dooley S (2007) Profibrogenic transforming growth factor-beta/activin receptor-like kinase 5 signaling via connective tissue growth factor expression in hepatocytes. Hepatology 46:1257–1270

    Article  CAS  PubMed  Google Scholar 

  204. Nakamura T, Sakata R, Ueno T, Sata M, Ueno H (2000) Inhibition of transforming growth factor beta prevents progression of liver fibrosis and enhances hepatocyte regeneration in dimethylnitrosamine-treated rats. Hepatology 32:247–255

    Article  CAS  PubMed  Google Scholar 

  205. Kanzler S, Lohse AW, Keil A, Henninger J, Dienes HP, Schirmacher P, Rose-John S, Buschenfelde KH, Blessing M (1999) TGF-beta1 in liver fibrosis: an inducible transgenic mouse model to study liver fibrogenesis. Am J Physiol 276:G1059–G1068

    CAS  PubMed  Google Scholar 

  206. Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MA Jr, Wrana JL, Falb D (1997) The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell 89:1165–1173

    Article  CAS  PubMed  Google Scholar 

  207. Tahashi Y, Matsuzaki K, Date M, Yoshida K, Furukawa F, Sugano Y, Matsushita M, Himeno Y, Inagaki Y, Inoue K (2002) Differential regulation of TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injury. Hepatology 35:49–61

    Article  CAS  PubMed  Google Scholar 

  208. Yan X, Lin Z, Chen F, Zhao X, Chen H, Ning Y, Chen YG (2009) Human BAMBI cooperates with Smad7 to inhibit transforming growth factor-beta signaling. J Biol Chem 284:30097–30104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Liu C, Chen X, Yang L, Kisseleva T, Brenner DA, Seki E (2014) Transcriptional repression of the transforming growth factor beta (TGF-beta) pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI) by nuclear factor kappaB (NF-kappaB) p50 enhances TGF-beta signaling in hepatic stellate cells. J Biol Chem 289:7082–7091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, Pellicoro A, Raschperger E, Betsholtz C, Ruminski PG, Griggs DW, Prinsen MJ, Maher JJ, Iredale JP, Lacy-Hulbert A, Adams RH, Sheppard D (2013) Targeting of alphav integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 19:1617–1624

    Article  CAS  PubMed  Google Scholar 

  211. Saile B, Matthes N, Knittel T, Ramadori G (1999) Transforming growth factor beta and tumor necrosis factor alpha inhibit both apoptosis and proliferation of activated rat hepatic stellate cells. Hepatology 30:196–202

    Article  CAS  PubMed  Google Scholar 

  212. Omenetti A, Choi S, Michelotti G, Diehl AM (2011) Hedgehog signaling in the liver. J Hepatol 54:366–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Guy CD, Suzuki A, Zdanowicz M, Abdelmalek MF, Burchette J, Unalp A, Diehl AM (2012) Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology 55:1711–1721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Swiderska-Syn M, Suzuki A, Guy CD, Schwimmer JB, Abdelmalek MF, Lavine JE, Diehl AM (2013) Hedgehog pathway and pediatric nonalcoholic fatty liver disease. Hepatology 57:1814–1825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Choi SS, Witek RP, Yang L, Omenetti A, Syn WK, Moylan CA, Jung Y, Karaca GF, Teaberry VS, Pereira TA, Wang J, Ren XR, Diehl AM (2010) Activation of Rac1 promotes hedgehog-mediated acquisition of the myofibroblastic phenotype in rat and human hepatic stellate cells. Hepatology 52:278–290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Xie G, Karaca G, Swiderska-Syn M, Michelotti GA, Kruger L, Chen Y, Premont RT, Choi SS, Diehl AM (2013) Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice. Hepatology 58:1801–1813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Aleffi S, Petrai I, Bertolani C, Parola M, Colombatto S, Novo E, Vizzutti F, Anania FA, Milani S, Rombouts K, Laffi G, Pinzani M, Marra F (2005) Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology 42:1339–1348

    Article  CAS  PubMed  Google Scholar 

  218. Saxena NK, Titus MA, Ding X, Floyd J, Srinivasan S, Sitaraman SV, Anania FA (2004) Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylation. FASEB J 18:1612–1614

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Gao B (2005) Cytokines, STATs and liver disease. Cell Mol Immunol 2:92–100

    CAS  PubMed  Google Scholar 

  220. Kamada Y, Tamura S, Kiso S, Matsumoto H, Saji Y, Yoshida Y, Fukui K, Maeda N, Nishizawa H, Nagaretani H, Okamoto Y, Kihara S, Miyagawa J, Shinomura Y, Funahashi T, Matsuzawa Y (2003) Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin. Gastroenterology 125:1796–1807

    Article  CAS  PubMed  Google Scholar 

  221. Seo YS, Shah VH (2012) The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension. Clin Mol Hepatol 18:337–346

    Article  PubMed  PubMed Central  Google Scholar 

  222. Keshavarzian A, Holmes EW, Patel M, Iber F, Fields JZ, Pethkar S (1999) Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage. Am J Gastroenterol 94:200–207

    Article  CAS  PubMed  Google Scholar 

  223. Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA, Schwabe RF (2007) TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 13:1324–1332

    Article  CAS  PubMed  Google Scholar 

  224. Mazagova M, Wang L, Anfora AT, Wissmueller M, Lesley SA, Miyamoto Y, Eckmann L, Dhungana S, Pathmasiri W, Sumner S, Westwater C, Brenner DA, Schnabl B (2015) Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J 29:1043–1055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. De Minicis S, Rychlicki C, Agostinelli L, Saccomanno S, Candelaresi C, Trozzi L, Mingarelli E, Facinelli B, Magi G, Palmieri C, Marzioni M, Benedetti A, Svegliati-Baroni G (2014) Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology 59:1738–1749

    Article  PubMed  CAS  Google Scholar 

  226. Cengiz M, Ozenirler S, Elbeg S (2015) Role of serum toll-like receptors 2 and 4 in non-alcoholic steatohepatitis and liver fibrosis. J Gastroenterol Hepatol 30:1190–1196

    Article  CAS  PubMed  Google Scholar 

  227. Hernandez-Gea V, Ghiassi-Nejad Z, Rozenfeld R, Gordon R, Fiel MI, Yue Z, Czaja MJ, Friedman SL (2012) Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142:938–946

    Article  PubMed  PubMed Central  Google Scholar 

  228. Yang L, Kwon J, Popov Y, Gajdos GB, Ordog T, Brekken RA, Mukhopadhyay D, Schuppan D, Bi Y, Simonetto D, Shah VH (2014) Vascular endothelial growth factor promotes fibrosis resolution and repair in mice. Gastroenterology 146(1339–1350):e1331

    Google Scholar 

  229. Kaur S, Anita K (2013) Angiogenesis in liver regeneration and fibrosis: “a double-edged sword”. Hepatol Int 7:959–968

    Article  PubMed  Google Scholar 

  230. Fernandez M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J (2009) Angiogenesis in liver disease. J Hepatol 50:604–620

    Article  CAS  PubMed  Google Scholar 

  231. Kitade M, Yoshiji H, Kojima H, Ikenaka Y, Noguchi R, Kaji K, Yoshii J, Yanase K, Namisaki T, Asada K, Yamazaki M, Tsujimoto T, Akahane T, Uemura M, Fukui H (2006) Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats. Hepatology 44:983–991

    Article  CAS  PubMed  Google Scholar 

  232. Qu A, Taylor M, Xue X, Matsubara T, Metzger D, Chambon P, Gonzalez FJ, Shah YM (2011) Hypoxia-inducible transcription factor 2alpha promotes steatohepatitis through augmenting lipid accumulation, inflammation, and fibrosis. Hepatology 54:472–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Novo E, Cannito S, Zamara E, Valfre di Bonzo L, Caligiuri A, Cravanzola C, Compagnone A, Colombatto S, Marra F, Pinzani M, Parola M (2007) Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. Am J Pathol 170:1942–1953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Taura K, De Minicis S, Seki E, Hatano E, Iwaisako K, Osterreicher CH, Kodama Y, Miura K, Ikai I, Uemoto S, Brenner DA (2008) Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology 135:1729–1738

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Pediatrics, Digestive Diseases and Nutrition Center, Women and Children’s Hospital of Buffalo, The State University of New York at Buffalo (SUNY Buffalo), 3435 Main Street, 422 BRB, Buffalo, NY, 14214, USA

    Wensheng Liu, Robert D. Baker, Tavleen Bhatia, Lixin Zhu & Susan S. Baker

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Liu, W., Baker, R.D., Bhatia, T. et al. Pathogenesis of nonalcoholic steatohepatitis. Cell. Mol. Life Sci. 73, 1969–1987 (2016). https://doi.org/10.1007/s00018-016-2161-x

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