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Abstract

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches based on a profound understanding of its pathogenesis to halt disease progression to advanced fibrosis or cirrhosis and cancer. The pathogenesis of NAFLD involves a complex interaction among environmental factors (i.e., Western diet), obesity, changes in microbiota, and predisposing genetic variants resulting in a disturbed lipid homeostasis and an excessive accumulation of triglycerides and other lipid species in hepatocytes. Insulin resistance is a central mechanism that leads to lipotoxicity, endoplasmic reticulum stress, disturbed autophagy, and, ultimately, hepatocyte injury and death that triggers hepatic inflammation, hepatic stellate cell activation, and progressive fibrogenesis, thus driving disease progression. In the present review, we summarize the currently available data on the pathogenesis of NAFLD, emphasizing the most recent advances. A better understanding of NAFLD/NASH pathogenesis is crucial for the design of new and efficient therapeutic interventions.

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2018-01-24
2024-03-28
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Literature Cited

  1. Brunt EM. 1.  2010. Pathology of nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 7:195–203 [Google Scholar]
  2. Brunt EM, Wong VW, Nobili V, Day CP, Sookoian S. 2.  et al. 2015. Nonalcoholic fatty liver disease. Nat. Rev. Dis. Primers 1:15080 [Google Scholar]
  3. 3.  Eur. Assoc. Study Liver, Eur. Assoc. Study Diabetes, Eur. Assoc. Study Obes. 2016. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J. Hepatol. 64:1388–402 [Google Scholar]
  4. Vanni E, Marengo A, Mezzabotta L, Bugianesi E. 4.  2015. Systemic complications of nonalcoholic fatty liver disease: when the liver is not an innocent bystander. Semin. Liver Dis. 35:236–49 [Google Scholar]
  5. Satapathy SK, Sanyal AJ. 5.  2015. Epidemiology and natural history of nonalcoholic fatty liver disease. Semin. Liver Dis. 35:221–35 [Google Scholar]
  6. Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES. 6.  et al. 2015. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149:389–97.e10 [Google Scholar]
  7. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. 7.  2016. Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64:73–84 [Google Scholar]
  8. Goh GB, McCullough AJ. 8.  2016. Natural history of nonalcoholic fatty liver disease. Dig. Dis. Sci. 61:1226–33 [Google Scholar]
  9. Argo CK, Caldwell SH. 9.  2009. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin. Liver Dis. 13:511–31 [Google Scholar]
  10. Arab JP, Barrera F, Gallego C, Valderas JP, Uribe S. 10.  et al. 2016. High prevalence of undiagnosed liver cirrhosis and advanced fibrosis in type 2 diabetic patients. Ann. Hepatol. 15:721–28 [Google Scholar]
  11. Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. 11.  2011. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 141:1249–53 [Google Scholar]
  12. Siow W, van der Poorten D, George J. 12.  2016. Epidemiological trends in NASH as a cause for liver transplant. Curr. Hepatol. Rep. 15:67–74 [Google Scholar]
  13. Mittal S, El-Serag HB, Sada YH, Kanwal F, Duan Z. 13.  et al. 2016. Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 14:1124–31.e1 [Google Scholar]
  14. Beste LA, Leipertz SL, Green PK, Dominitz JA, Ross D, Ioannou GN. 14.  2015. Trends in burden of cirrhosis and hepatocellular carcinoma by underlying liver disease in US veterans, 2001–2013. Gastroenterology 149:1471–82.e5 [Google Scholar]
  15. Piscaglia F, Svegliati-Baroni G, Barchetti A, Pecorelli A, Marinelli S. 15.  et al. 2016. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology 63:827–38 [Google Scholar]
  16. Musso G, Cassader M, Gambino R. 16.  2016. Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies. Nat. Rev. Drug. Discov. 15:249–74 [Google Scholar]
  17. Buzzetti E, Pinzani M, Tsochatzis EA. 17.  2016. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 65:1038–48 [Google Scholar]
  18. McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. 18.  2015. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J. Hepatol. 62:1148–55 [Google Scholar]
  19. Hardy T, Oakley F, Anstee QM, Day CP. 19.  2016. Nonalcoholic fatty liver disease: pathogenesis and disease spectrum. Annu. Rev. Pathol. 11:451–96 [Google Scholar]
  20. Anstee QM, Targher G, Day CP. 20.  2013. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat. Rev. Gastroenterol. Hepatol. 10:330–44 [Google Scholar]
  21. Berk PD. 21.  2008. Regulatable fatty acid transport mechanisms are central to the pathophysiology of obesity, fatty liver, and metabolic syndrome. Hepatology 48:1362–76 [Google Scholar]
  22. Hubbard B, Doege H, Punreddy S, Wu H, Huang X. 22.  et al. 2006. Mice deleted for fatty acid transport protein 5 have defective bile acid conjugation and are protected from obesity. Gastroenterology 130:1259–69 [Google Scholar]
  23. Doege H, Grimm D, Falcon A, Tsang B, Storm TA. 23.  et al. 2008. Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia. J. Biol. Chem. 283:22186–92 [Google Scholar]
  24. Berlanga A, Guiu-Jurado E, Porras JA, Auguet T. 24.  2014. Molecular pathways in non-alcoholic fatty liver disease. Clin. Exp. Gastroenterol. 7:221–39 [Google Scholar]
  25. Greco D, Kotronen A, Westerbacka J, Puig O, Arkkila P. 25.  et al. 2008. Gene expression in human NAFLD. Am. J. Physiol. Gastrointest. Liver Physiol. 294:G1281–87 [Google Scholar]
  26. Bechmann LP, Gieseler RK, Sowa JP, Kahraman A, Erhard J. 26.  et al. 2010. Apoptosis is associated with CD36/fatty acid translocase upregulation in non-alcoholic steatohepatitis. Liver Int 30:850–59 [Google Scholar]
  27. Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. 27.  2014. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology 146:726–35 [Google Scholar]
  28. Cha JY, Repa JJ. 28.  2007. The liver X receptor (LXR) and hepatic lipogenesis. The carbohydrate-response element-binding protein is a target gene of LXR. J. Biol. Chem. 282:743–51 [Google Scholar]
  29. Mitro N, Mak PA, Vargas L, Godio C, Hampton E. 29.  et al. 2007. The nuclear receptor LXR is a glucose sensor. Nature 445:219–23 [Google Scholar]
  30. Softic S, Cohen DE, Kahn CR. 30.  2016. Role of dietary fructose and hepatic de novo lipogenesis in fatty liver disease. Dig. Dis. Sci. 61:1282–93 [Google Scholar]
  31. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. 31.  2005. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Investig. 115:1343–51 [Google Scholar]
  32. McGarry JD, Brown NF. 32.  1997. The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur. J. Biochem. 244:1–14 [Google Scholar]
  33. Rogue A, Lambert C, Josse R, Antherieu S, Spire C. 33.  et al. 2011. Comparative gene expression profiles induced by PPARγ and PPARα/γ agonists in human hepatocytes. PLOS ONE 6:e18816 [Google Scholar]
  34. Nguyen P, Leray V, Diez M, Serisier S, Le Bloc'h J. 34.  et al. 2008. Liver lipid metabolism. J. Anim. Physiol. Anim. Nutr. 92:272–83 [Google Scholar]
  35. Reddy JK. 35.  2001. Nonalcoholic steatosis and steatohepatitis. III. Peroxisomal beta-oxidation, PPARα, and steatohepatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 281:G1333–39 [Google Scholar]
  36. Kawano Y, Cohen DE. 36.  2013. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J. Gastroenterol. 48:434–41 [Google Scholar]
  37. Sabio G, Das M, Mora A, Zhang Z, Jun JY. 37.  et al. 2008. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322:1539–43 [Google Scholar]
  38. Yamauchi T, Hara K, Kubota N, Terauchi Y, Tobe K. 38.  et al. 2003. Dual roles of adiponectin/Acrp30 in vivo as an anti-diabetic and anti-atherogenic adipokine. Curr. Drug Targets Immune Endocr. Metabol. Disord. 3:243–54 [Google Scholar]
  39. Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. 39.  2003. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J. Clin. Investig. 112:91–100 [Google Scholar]
  40. Kumashiro N, Erion DM, Zhang D, Kahn M, Beddow SA. 40.  et al. 2011. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. PNAS 108:16381–85 [Google Scholar]
  41. Hirsova P, Ibrahim SH, Gores GJ, Malhi H. 41.  2016. Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis. J. Lipid Res. 57:1758–70 [Google Scholar]
  42. Trauner M, Arrese M, Wagner M. 42.  2010. Fatty liver and lipotoxicity. Biochim. Biophys. Acta 1801:299–310 [Google Scholar]
  43. Neuschwander-Tetri BA. 43.  2010. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology 52:774–88 [Google Scholar]
  44. Hirsova P, Gores GJ. 44.  2015. Death receptor-mediated cell death and proinflammatory signaling in nonalcoholic steatohepatitis. Cell Mol. Gastroenterol. Hepatol. 1:17–27 [Google Scholar]
  45. Li ZZ, Berk M, McIntyre TM, Feldstein AE. 45.  2009. Hepatic lipid partitioning and liver damage in nonalcoholic fatty liver disease: role of stearoyl-CoA desaturase. J. Biol. Chem. 284:5637–44 [Google Scholar]
  46. Yamaguchi K, Yang L, McCall S, Huang J, Yu XX. 46.  et al. 2007. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 45:1366–74 [Google Scholar]
  47. Yamaguchi K, Yang L, McCall S, Huang J, Yu XX. 47.  et al. 2008. Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis. Hepatology 47:625–35 [Google Scholar]
  48. Koliaki C, Szendroedi J, Kaul K, Jelenik T, Nowotny P. 48.  et al. 2015. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab 21:739–46 [Google Scholar]
  49. Arguello G, Balboa E, Arrese M, Zanlungo S. 49.  2015. Recent insights on the role of cholesterol in non-alcoholic fatty liver disease. Biochim. Biophys. Acta 1852:1765–78 [Google Scholar]
  50. Robertson G, Leclercq I, Farrell GC. 50.  2001. Nonalcoholic steatosis and steatohepatitis. II. Cytochrome P-450 enzymes and oxidative stress. Am. J. Physiol. Gastrointest. Liver Physiol. 281:G1135–39 [Google Scholar]
  51. Bellanti F, Villani R, Facciorusso A, Vendemiale G, Serviddio G. 51.  2017. Lipid oxidation products in the pathogenesis of non-alcoholic steatohepatitis. Free Radic. Biol. Med. 111:173–85 [Google Scholar]
  52. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ. 52.  et al. 2001. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120:1183–92 [Google Scholar]
  53. MacDonald GA, Bridle KR, Ward PJ, Walker NI, Houglum K. 53.  et al. 2001. Lipid peroxidation in hepatic steatosis in humans is associated with hepatic fibrosis and occurs predominately in acinar zone 3. J. Gastroenterol. Hepatol. 16:599–606 [Google Scholar]
  54. Handa P, Morgan-Stevenson V, Maliken BD, Nelson JE, Washington S. 54.  et al. 2016. Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice. Am. J. Physiol. Gastrointest. Liver Physiol. 310:G117–27 [Google Scholar]
  55. Hoki T, Miyanishi K, Tanaka S, Takada K, Kawano Y. 55.  et al. 2015. Increased duodenal iron absorption through upregulation of divalent metal transporter 1 from enhancement of iron regulatory protein 1 activity in patients with nonalcoholic steatohepatitis. Hepatology 62:3751–61 [Google Scholar]
  56. Maliken BD, Nelson JE, Klintworth HM, Beauchamp M, Yeh MM, Kowdley KV. 56.  2013. Hepatic reticuloendothelial system cell iron deposition is associated with increased apoptosis in nonalcoholic fatty liver disease. Hepatology 57:51806–13 [Google Scholar]
  57. Kowdley KV, Belt P, Wilson LA, Yeh MM, Neuschwander-Tetri BA. 57.  et al. 2012. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 55:177–85 [Google Scholar]
  58. Puri P, Mirshahi F, Cheung O, Natarajan R, Maher JW. 58.  et al. 2008. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 134:568–76 [Google Scholar]
  59. Malhi H, Kaufman RJ. 59.  2011. Endoplasmic reticulum stress in liver disease. J. Hepatol. 54:795–809 [Google Scholar]
  60. Tilg H, Moschen AR. 60.  2010. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52:1836–46 [Google Scholar]
  61. Hotamisligil GS. 61.  2010. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140:900–17 [Google Scholar]
  62. Kumar H, Kawai T, Akira S. 62.  2011. Pathogen recognition by the innate immune system. Int. Rev. Immunol. 30:16–34 [Google Scholar]
  63. Seki E, Brenner DA. 63.  2008. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 48:322–35 [Google Scholar]
  64. Crispe IN. 64.  2009. The liver as a lymphoid organ. Annu. Rev. Immunol. 27:147–63 [Google Scholar]
  65. Guo J, Friedman SL. 65.  2010. Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis. Fibrogenesis Tissue Repair 3:21 [Google Scholar]
  66. Petrasek J, Mandrekar P, Szabo G. 66.  2010. Toll-like receptors in the pathogenesis of alcoholic liver disease. Gastroenterol. Res. Pract. 2010:710381 [Google Scholar]
  67. Szabo G, Dolganiuc A, Mandrekar P. 67.  2006. Pattern recognition receptors: a contemporary view on liver diseases. Hepatology 44:287–98 [Google Scholar]
  68. Takeuchi O, Akira S. 68.  2010. Pattern recognition receptors and inflammation. Cell 140:805–20 [Google Scholar]
  69. Mandrekar P, Szabo G. 69.  2009. Signalling pathways in alcohol-induced liver inflammation. J. Hepatol. 50:1258–66 [Google Scholar]
  70. Verstak B, Nagpal K, Bottomley SP, Golenbock DT, Hertzog PJ, Mansell A. 70.  2009. MyD88 adapter-like (Mal)/TIRAP interaction with TRAF6 is critical for TLR2- and TLR4-mediated NF-κB proinflammatory responses. J. Biol. Chem. 284:24192–203 [Google Scholar]
  71. Akira S, Uematsu S, Takeuchi O. 71.  2006. Pathogen recognition and innate immunity. Cell 124:783–801 [Google Scholar]
  72. Seki E, Schnabl B. 72.  2012. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J. Physiol. 590:447–58 [Google Scholar]
  73. Schafer SL, Lin R, Moore PA, Hiscott J, Pitha PM. 73.  1998. Regulation of type I interferon gene expression by interferon regulatory factor–3. J. Biol. Chem. 273:2714–20 [Google Scholar]
  74. Miura K, Kodama Y, Inokuchi S, Schnabl B, Aoyama T. 74.  et al. 2010. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1β in mice. Gastroenterology 139:323–34.e7 [Google Scholar]
  75. Petrasek J, Dolganiuc A, Csak T, Kurt-Jones EA, Szabo G. 75.  2011. Type I interferons protect from Toll-like receptor 9–associated liver injury and regulate IL-1 receptor antagonist in mice. Gastroenterology 140:697708.e4 [Google Scholar]
  76. Arrese M, Cabrera D, Kalergis AM, Feldstein AE. 76.  2016. Innate immunity and inflammation in NAFLD/NASH. Dig. Dis. Sci. 61:1294–303 [Google Scholar]
  77. Chen GY, Nunez G. 77.  2010. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10:826–37 [Google Scholar]
  78. Ye D, Li FY, Lam KS, Li H, Jia W. 78.  et al. 2012. Toll-like receptor–4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice. Gut 61:1058–67 [Google Scholar]
  79. Tang Y, Bian Z, Zhao L, Liu Y, Liang S. 79.  et al. 2011. Interleukin-17 exacerbates hepatic steatosis and inflammation in non-alcoholic fatty liver disease. Clin. Exp. Immunol. 166:281–90 [Google Scholar]
  80. Hirsova P, Ibrahim SH, Verma VK, Morton LA, Shah VH. 80.  et al. 2016. Extracellular vesicles in liver pathobiology: small particles with big impact. Hepatology 64:2219–33 [Google Scholar]
  81. Povero D, Feldstein AE. 81.  2016. Novel molecular mechanisms in the development of non-alcoholic steatohepatitis. Diabetes Metab. J. 40:11–11 [Google Scholar]
  82. Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ. 82.  et al. 2003. Hepatocyte apoptosis and Fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125:437–43 [Google Scholar]
  83. Malhi H, Barreyro FJ, Isomoto H, Bronk SF, Gores GJ. 83.  2007. Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity. Gut 56:1124–31 [Google Scholar]
  84. Crespo J, Cayon A, Fernandez-Gil P, Hernandez-Guerra M, Mayorga M. 84.  et al. 2001. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 34:1158–63 [Google Scholar]
  85. McClain CJ, Barve S, Deaciuc I. 85.  2007. Good fat/bad fat. Hepatology 45:1343–46 [Google Scholar]
  86. Arab JP, Hernandez-Rocha C, Morales C, Vargas JI, Solis N. 86.  et al. 2017. Serum cytokeratin-18 fragment levels as noninvasive marker of nonalcoholic steatohepatitis in the Chilean population. Gastroenterol. Hepatol. 40:6388–94 [Google Scholar]
  87. Wieckowska A, Zein NN, Yerian LM, Lopez AR, McCullough AJ, Feldstein AE. 87.  2006. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology 44:27–33 [Google Scholar]
  88. Gautheron J, Vucur M, Reisinger F, Cardenas DV, Roderburg C. 88.  et al. 2014. A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis. EMBO Mol. Med. 6:1062–74 [Google Scholar]
  89. Wree A, Eguchi A, McGeough MD, Pena CA, Johnson CD. 89.  et al. 2014. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology 59:898–910 [Google Scholar]
  90. Czaja MJ. 90.  2016. Function of autophagy in nonalcoholic fatty liver disease. Dig. Dis. Sci. 61:1304–13 [Google Scholar]
  91. Mei S, Ni HM, Manley S, Bockus A, Kassel KM. 91.  et al. 2011. Differential roles of unsaturated and saturated fatty acids on autophagy and apoptosis in hepatocytes. J. Pharmacol. Exp. Ther. 339:487–98 [Google Scholar]
  92. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I. 92.  et al. 2009. Autophagy regulates lipid metabolism. Nature 458:1131–35 [Google Scholar]
  93. Martinez-Lopez N, Singh R. 93.  2015. Autophagy and lipid droplets in the liver. Annu. Rev. Nutr. 35:215–37 [Google Scholar]
  94. Schulz RJ, Sathyanarayan A, Mashek DG. 94.  2017. Breaking fat: the regulation and mechanisms of lipophagy. Biochim. Biophys. Acta 1862:1178–87 [Google Scholar]
  95. Kim KH, Jeong YT, Oh H, Kim SH, Cho JM. 95.  et al. 2013. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat. Med 19:183–92 [Google Scholar]
  96. Higashi T, Friedman SL, Hoshida Y. 96.  2017. Hepatic stellate cells as key target in liver fibrosis. Adv. Drug Deliv. Rev. In press. https://doi.org/10.1016/j.addr.2017.05.007 [Crossref]
  97. Puche JE, Saiman Y, Friedman SL. 97.  2013. Hepatic stellate cells and liver fibrosis. Compr. Physiol. 3:1473–92 [Google Scholar]
  98. Koyama Y, Brenner DA. 98.  2017. Liver inflammation and fibrosis. J. Clin. Investig. 127:55–64 [Google Scholar]
  99. Trautwein C, Friedman SL, Schuppan D, Pinzani M. 99.  2015. Hepatic fibrosis: concept to treatment. J. Hepatol. 62:S15–24 [Google Scholar]
  100. Lee YA, Wallace MC, Friedman SL. 100.  2015. Pathobiology of liver fibrosis: a translational success story. Gut 64:830–41 [Google Scholar]
  101. Marra F, Provenzano A, Vivoli E. 101.  2014. Mechanisms of fibrosis in steatohepatitis. Curr. Hepatol. Rep. 13:142–50 [Google Scholar]
  102. Friedman SL. 102.  2013. Liver fibrosis in 2012: convergent pathways that cause hepatic fibrosis in NASH. Nat. Rev. Gastroenterol. Hepatol. 10:71–72 [Google Scholar]
  103. Paradis V, Perlemuter G, Bonvoust F, Dargere D, Parfait B. 103.  et al. 2001. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 34:738–44 [Google Scholar]
  104. Cai CX, Buddha H, Castelino-Prabhu S, Zhang Z, Britton RS. 104.  et al. 2017. Activation of insulin-PI3K/Akt-p70S6K pathway in hepatic stellate cells contributes to fibrosis in nonalcoholic steatohepatitis. Dig. Dis. Sci. 62:968–78 [Google Scholar]
  105. Jiang JX, Chen X, Fukada H, Serizawa N, Devaraj S, Torok NJ. 105.  2013. Advanced glycation endproducts induce fibrogenic activity in nonalcoholic steatohepatitis by modulating TNF-α-converting enzyme activity in mice. Hepatology 58:1339–48 [Google Scholar]
  106. Cusi K. 106.  2016. Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current approaches and future directions. Diabetologia 59:1112–20 [Google Scholar]
  107. Saxena NK, Anania FA. 107.  2015. Adipocytokines and hepatic fibrosis. Trends Endocrinol. Metab. 26:153–61 [Google Scholar]
  108. Ramezani-Moghadam M, Wang J, Ho V, Iseli TJ, Alzahrani B. 108.  et al. 2015. Adiponectin reduces hepatic stellate cell migration by promoting tissue inhibitor of metalloproteinase-1 (TIMP-1) secretion. J. Biol. Chem. 290:5533–42 [Google Scholar]
  109. Park PH, Sanz-Garcia C, Nagy LE. 109.  2015. Adiponectin as an anti-fibrotic and anti-inflammatory adipokine in the liver. Curr. Pathobiol. Rep. 3:243–52 [Google Scholar]
  110. Nazal L, Riquelme A, Solis N, Pizarro M, Escalona A. 110.  et al. 2010. Hypoadiponectinemia and its association with liver fibrosis in morbidly obese patients. Obes. Surg. 20:1400–7 [Google Scholar]
  111. Gan LT, Van Rooyen DM, Koina ME, McCuskey RS, Teoh NC, Farrell GC. 111.  2014. Hepatocyte free cholesterol lipotoxicity results from JNK1-mediated mitochondrial injury and is HMGB1 and TLR4-dependent. J. Hepatol. 61:1376–84 [Google Scholar]
  112. Ioannou GN, Haigh WG, Thorning D, Savard C. 112.  2013. Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis. J. Lipid Res. 54:1326–34 [Google Scholar]
  113. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G. 113.  et al. 2010. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464:1357–61 [Google Scholar]
  114. Rajamaki K, Lappalainen J, Oorni K, Valimaki E, Matikainen S. 114.  et al. 2010. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLOS ONE 5:e11765 [Google Scholar]
  115. Tomita K, Teratani T, Suzuki T, Shimizu M, Sato H. 115.  et al. 2014. Free cholesterol accumulation in hepatic stellate cells: mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatology 59:154–69 [Google Scholar]
  116. Tomita K, Teratani T, Suzuki T, Shimizu M, Sato H. 116.  et al. 2014. Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells. J. Hepatol. 61:98–106 [Google Scholar]
  117. Boursier J, Mueller O, Barret M, Machado M, Fizanne L. 117.  et al. 2016. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 63:764–75 [Google Scholar]
  118. Brandl K, Schnabl B. 118.  2017. Intestinal microbiota and nonalcoholic steatohepatitis. Curr. Opin. Gastroenterol. 33:128–33 [Google Scholar]
  119. Haslam DB. 119.  2017. Nonalcoholic steatohepatitis and the intestinal microbiota. Hepatology 65:401–3 [Google Scholar]
  120. De Minicis S, Rychlicki C, Agostinelli L, Saccomanno S, Candelaresi C. 120.  et al. 2014. Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology 59:1738–49 [Google Scholar]
  121. Bigorgne AE, John B, Ebrahimkhani MR, Shimizu-Albergine M, Campbell JS, Crispe IN. 121.  2016. TLR4-dependent secretion by hepatic stellate cells of the neutrophil-chemoattractant CXCL1 mediates liver response to gut microbiota. PLOS ONE 11:e0151063 [Google Scholar]
  122. Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ. 122.  et al. 2012. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482:179–85 [Google Scholar]
  123. Mridha AR, Wree A, Robertson AAB, Yeh MM, Johnson CD. 123.  et al. 2017. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J. Hepatol. 66:1037–46 [Google Scholar]
  124. Leclercq IA, Farrell GC, Schriemer R, Robertson GR. 124.  2002. Leptin is essential for the hepatic fibrogenic response to chronic liver injury. J. Hepatol. 37:206–13 [Google Scholar]
  125. Marra F. 125.  2007. Leptin and liver tissue repair: Do rodent models provide the answers?. J. Hepatol. 46:12–18 [Google Scholar]
  126. Jiang JX, Mikami K, Shah VH, Torok NJ. 126.  2008. Leptin induces phagocytosis of apoptotic bodies by hepatic stellate cells via a Rho guanosine triphosphatase-dependent mechanism. Hepatology 48:1497–505 [Google Scholar]
  127. Wang J, Leclercq I, Brymora JM, Xu N, Ramezani-Moghadam M. 127.  et al. 2009. Kupffer cells mediate leptin-induced liver fibrosis. Gastroenterology 137:713–23 [Google Scholar]
  128. D'Incao RB, Tovo CV, Mattevi VS, Borges DO, Ulbrich JM. 128.  et al. 2017. Adipokine levels versus hepatic histopathology in bariatric surgery patients. Obes. Surg. 27:82151–58 [Google Scholar]
  129. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. 129.  1995. A novel serum protein similar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270:26746–49 [Google Scholar]
  130. Flechtner-Mors M, George SN, Oeztuerk S, Haenle MM, Koenig W. 130.  et al. (EMIL-Study group). 2014. Association of adiponectin with hepatic steatosis: a study of 1,349 subjects in a random population sample. BMC Res. Notes 7:207 [Google Scholar]
  131. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T. 131.  et al. 2003. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423:762–69 [Google Scholar]
  132. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N. 132.  et al. 2001. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat. Med. 7:941–46 [Google Scholar]
  133. Tsao TS, Murrey HE, Hug C, Lee DH, Lodish HF. 133.  2002. Oligomerization state-dependent activation of NF-κB signaling pathway by adipocyte complement-related protein of 30 kDa (Acrp30). J. Biol. Chem. 277:29359–62 [Google Scholar]
  134. Masaki T, Chiba S, Tatsukawa H, Yasuda T, Noguchi H. 134.  et al. 2004. Adiponectin protects LPS-induced liver injury through modulation of TNF-α in KK-Ay obese mice. Hepatology 40:177–84 [Google Scholar]
  135. Awazawa M, Ueki K, Inabe K, Yamauchi T, Kaneko K. 135.  et al. 2009. Adiponectin suppresses hepatic SREBP1c expression in an AdipoR1/LKB1/AMPK dependent pathway. Biochem. Biophys. Res. Commun. 382:51–56 [Google Scholar]
  136. Oral EA, Javor ED, Ding L, Uzel G, Cochran EK. 136.  et al. 2006. Leptin replacement therapy modulates circulating lymphocyte subsets and cytokine responsiveness in severe lipodystrophy. J. Clin. Endocrinol. Metab. 91:621–28 [Google Scholar]
  137. Caligiuri A, Bertolani C, Guerra CT, Aleffi S, Galastri S. 137.  et al. 2008. Adenosine monophosphate-activated protein kinase modulates the activated phenotype of hepatic stellate cells. Hepatology 47:668–76 [Google Scholar]
  138. Stefan N, Haring HU. 138.  2013. The role of hepatokines in metabolism. Nat. Rev. Endocrinol. 9:144–52 [Google Scholar]
  139. Biedermann L, Rogler G. 139.  2015. The intestinal microbiota: its role in health and disease. Eur. J. Pediatr. 174:151–67 [Google Scholar]
  140. Bluemel S, Williams B, Knight R, Schnabl B. 140.  2016. Precision medicine in alcoholic and nonalcoholic fatty liver disease via modulating the gut microbiota. Am. J. Physiol. Gastrointest. Liver Physiol. 311:G1018–36 [Google Scholar]
  141. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. 141.  2006. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444:1027–31 [Google Scholar]
  142. Topping DL, Clifton PM. 142.  2001. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol. Rev. 81:1031–64 [Google Scholar]
  143. Spencer MD, Hamp TJ, Reid RW, Fischer LM, Zeisel SH, Fodor AA. 143.  2011. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology 140:976–86 [Google Scholar]
  144. Arab JP, Karpen SJ, Dawson PA, Arrese M, Trauner M. 144.  2017. Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives. Hepatology 65:350–62 [Google Scholar]
  145. Wieland A, Frank DN, Harnke B, Bambha K. 145.  2015. Systematic review: microbial dysbiosis and nonalcoholic fatty liver disease. Aliment. Pharmacol. Ther. 42:1051–63 [Google Scholar]
  146. Arab JP, Martin-Mateos RM, Shah VH. 146.  2017. Gut-liver axis, cirrhosis and portal hypertension: the chicken and the egg. Hepatol. Int. https://doi.org/10.1007/s12072-017-9798-x [Crossref]
  147. Leung C, Rivera L, Furness JB, Angus PW. 147.  2016. The role of the gut microbiota in NAFLD. Nat. Rev. Gastroenterol. Hepatol. 13:7412–25 [Google Scholar]
  148. Mao J-W, Tang H-Y, Zhao T, Tan X-Y, Bi J. 148.  et al. 2015. Intestinal mucosal barrier dysfunction participates in the progress of nonalcoholic fatty liver disease. Int. J. Clin. Exp. Pathol. 8:3648–58 [Google Scholar]
  149. Rahman K, Desai C, Iyer SS, Thorn NE, Kumar P. 149.  et al. 2016. Loss of junctional adhesion molecule A promotes severe steatohepatitis in mice on a diet high in saturated fat, fructose, and cholesterol. Gastroenterology 151:4733–46.e12 [Google Scholar]
  150. Miele L, Valenza V, La Torre G, Montalto M, Cammarota G. 150.  et al. 2009. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49:61877–87 [Google Scholar]
  151. Schneider KM, Bieghs V, Heymann F, Hu W, Dreymueller D. 151.  et al. 2015. CX3CR1 is a gatekeeper for intestinal barrier integrity in mice: limiting steatohepatitis by maintaining intestinal homeostasis. Hepatology 62:1405–16 [Google Scholar]
  152. Kirpich IA, Marsano LS, McClain CJ. 152.  2015. Gut-liver axis, nutrition, and non-alcoholic fatty liver disease. Clin. Biochem. 48:13–14923–30 [Google Scholar]
  153. Zhang Y, Lee FY, Barrera G, Lee H, Vales C. 153.  et al. 2006. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. PNAS 103:1006–11 [Google Scholar]
  154. Jahn D, Rau M, Hermanns HM, Geier A. 154.  2015. Mechanisms of enterohepatic fibroblast growth factor 15/19 signaling in health and disease. Cytokine Growth Factor Rev 26:625–35 [Google Scholar]
  155. Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ. 155.  2000. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102:731–44 [Google Scholar]
  156. Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ. 156.  et al. 2004. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J. Clin. Investig. 113:1408–18 [Google Scholar]
  157. Carr RM, Reid AE. 157.  2015. FXR agonists as therapeutic agents for non-alcoholic fatty liver disease. Curr. Atheroscler. Rep. 17:500–16 [Google Scholar]
  158. Fuchs CD, Traussnigg SA, Trauner M. 158.  2016. Nuclear receptor modulation for the treatment of nonalcoholic fatty liver disease. Semin. Liver Dis. 36:69–86 [Google Scholar]
  159. Mazuy C, Helleboid A, Staels B, Lefebvre P. 159.  2015. Nuclear bile acid signaling through the farnesoid X receptor. Cell Mol. Life Sci. 72:1631–50 [Google Scholar]
  160. Thomas C, Gioiello A, Noriega L, Strehle A, Oury J. 160.  et al. 2009. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 10:167–77 [Google Scholar]
  161. Ferrebee CB, Dawson PA. 161.  2015. Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids. Acta Pharm. Sin. B 5:129–34 [Google Scholar]
  162. Jiang C, Xie C, Lv Y, Li J, Krausz KW. 162.  et al. 2015. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat. Commun. 6:10166 [Google Scholar]
  163. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D. 163.  et al. 2008. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40:1461–65 [Google Scholar]
  164. Sookoian S, Castano GO, Burgueno AL, Gianotti TF, Rosselli MS, Pirola CJ. 164.  2009. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J. Lipid Res. 50:2111–16 [Google Scholar]
  165. Sookoian S, Pirola CJ. 165.  2011. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 53:1883–94 [Google Scholar]
  166. Trepo E, Romeo S, Zucman-Rossi J, Nahon P. 166.  2016. PNPLA3 gene in liver diseases. J. Hepatol. 65:399–412 [Google Scholar]
  167. Mancina RM, Matikainen N, Maglio C, Soderlund S, Lundbom N. 167.  et al. 2015. Paradoxical dissociation between hepatic fat content and de novo lipogenesis due to PNPLA3 sequence variant. J. Clin. Endocrinol. Metab. 100:E821–25 [Google Scholar]
  168. Pirazzi C, Adiels M, Burza MA, Mancina RM, Levin M. 168.  et al. 2012. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J. Hepatol. 57:1276–82 [Google Scholar]
  169. Liu YL, Patman GL, Leathart JB, Piguet AC, Burt AD. 169.  et al. 2014. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J. Hepatol. 61:75–81 [Google Scholar]
  170. Saab S, Manne V, Nieto J, Schwimmer JB, Chalasani NP. 170.  2016. Nonalcoholic fatty liver disease in Latinos. Clin. Gastroenterol. Hepatol. 14:5–12 [Google Scholar]
  171. Kalia HS, Gaglio PJ. 171.  2016. The prevalence and pathobiology of nonalcoholic fatty liver disease in patients of different races or ethnicities. Clin. Liver Dis. 20:215–24 [Google Scholar]
  172. Smagris E, BasuRay S, Li J, Huang Y, Lai KM. 172.  et al. 2015. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 61:108–18 [Google Scholar]
  173. Li JZ, Huang Y, Karaman R, Ivanova PT, Brown HA. 173.  et al. 2012. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J. Clin. Investig. 122:4130–44 [Google Scholar]
  174. Basantani MK, Sitnick MT, Cai L, Brenner DS, Gardner NP. 174.  et al. 2011. Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. J. Lipid Res. 52:318–29 [Google Scholar]
  175. Bruschi FV, Claudel T, Tardelli M, Caligiuri A, Stulnig TM. 175.  et al. 2017. The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells. Hepatology 65:1875–90 [Google Scholar]
  176. Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH. 176.  et al. 2014. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 46:352–56 [Google Scholar]
  177. Liu YL, Reeves HL, Burt AD, Tiniakos D, McPherson S. 177.  et al. 2014. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat. Commun. 5:4309 [Google Scholar]
  178. Dongiovanni P, Petta S, Maglio C, Fracanzani AL, Pipitone R. 178.  et al. 2015. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 61:506–14 [Google Scholar]
  179. Xu C, Wang G, Hao Y, Zhi J, Zhang L, Chang C. 179.  2011. Correlation analysis between gene expression profile of rat liver tissues and high-fat emulsion-induced nonalcoholic fatty liver. Dig. Dis. Sci. 56:2299–308 [Google Scholar]
  180. Magee N, Zou A, Zhang Y. 180.  2016. Pathogenesis of nonalcoholic steatohepatitis: interactions between liver parenchymal and nonparenchymal cells. Biomed. Res. Int. 2016:5170402 [Google Scholar]
  181. Cheung O, Puri P, Eicken C, Contos MJ, Mirshahi F. 181.  et al. 2008. Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression. Hepatology 48:1810–20 [Google Scholar]
  182. Marengo A, Rosso C, Bugianesi E. 182.  2016. Liver cancer: connections with obesity, fatty liver, and cirrhosis. Annu. Rev. Med. 67:103–17 [Google Scholar]
  183. Dyson J, Jaques B, Chattopadyhay D, Lochan R, Graham J. 183.  et al. 2014. Hepatocellular cancer: the impact of obesity, type 2 diabetes and a multidisciplinary team. J. Hepatol. 60:110–17 [Google Scholar]
  184. Vanni E, Bugianesi E. 184.  2014. Obesity and liver cancer. Clin. Liver Dis. 18:191–203 [Google Scholar]
  185. Budhu A, Roessler S, Zhao X, Yu Z, Forgues M. 185.  et al. 2013. Integrated metabolite and gene expression profiles identify lipid biomarkers associated with progression of hepatocellular carcinoma and patient outcomes. Gastroenterology 144:1066–75.e1 [Google Scholar]
  186. Montero J, Morales A, Llacuna L, Lluis JM, Terrones O. 186.  et al. 2008. Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma. Cancer Res 68:5246–56 [Google Scholar]
  187. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S. 187.  et al. 2013. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499:97–101 [Google Scholar]
  188. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM. 188.  et al. 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 55:2005–23 [Google Scholar]
  189. Sung KC, Ryu S, Lee JY, Kim JY, Wild SH, Byrne CD. 189.  2016. Effect of exercise on the development of new fatty liver and the resolution of existing fatty liver. J. Hepatol. 65:791–97 [Google Scholar]
  190. Shields WW, Thompson KE, Grice GA, Harrison SA, Coyle WJ. 190.  2009. The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a pilot trial. Ther. Adv. Gastroenterol. 2:157–63 [Google Scholar]
  191. Staels B, Rubenstrunk A, Noel B, Rigou G, Delataille P. 191.  et al. 2013. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 58:1941–52 [Google Scholar]
  192. Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P. 192.  et al. (GOLDEN-505 Investigator Study Group). 2016. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150:1147–59.e5 [Google Scholar]
  193. Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J. 193.  et al. 2016. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann. Intern. Med. 165:305–15 [Google Scholar]
  194. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM. 194.  et al. 2010. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362:1675–85 [Google Scholar]
  195. de Mesquita FC, Guixé-Muntet S, Rosa JL, Bosch J, de Oliveira JR, Gracia-Sancho J. 195.  2015. Deactivation of human and rat cirrhotic hepatic stellate cells: a novel alternative use for the glucagon-like 1 receptor agonist Liraglutide. Hepatology 62:901A [Google Scholar]
  196. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D. 196.  et al. 2016. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387:679–90 [Google Scholar]
  197. Cui J, Philo L, Nguyen P, Hofflich H, Hernandez C. 197.  et al. 2016. Sitagliptin versus placebo for non-alcoholic fatty liver disease: a randomized controlled trial. J. Hepatol. 65:369–76 [Google Scholar]
  198. Stiede K, Miao W, Blanchette HS, Beysen C, Harriman G. 198.  et al. 2017. Acetyl-CoA carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: a randomized, double-blind, crossover study. Hepatology 66:324–34 [Google Scholar]
  199. Bates J, Brockett R, Mikaelian I, Wang T, Ray A. 199.  et al. 2017. A liver-targeted acetyl CoA carboxylase inhibitor reduces hepatic steatosis and liver injury in a murine model of NASH. J. Hepatol. 66:S430 [Google Scholar]
  200. Gu Q, Paulose-Ram R, Burt VL, Kit BK. 200.  2014. Prescription cholesterol-lowering medication use in adults aged 40 and over: United States, 2003–2012 NCHS Data Brief 177 Natl. Cent. Health Stat. Atlanta, GA:
  201. Wong VW, Chitturi S, Wong GL, Yu J, Chan HL, Farrell GC. 201.  2016. Pathogenesis and novel treatment options for non-alcoholic steatohepatitis. Lancet Gastroenterol. Hepatol. 1:56–67 [Google Scholar]
  202. Athyros VG, Katsiki N, Karagiannis A, Mikhailidis DP. 202.  2016. Statins and non-alcoholic steatohepatitis. J. Hepatol. 64:241–42 [Google Scholar]
  203. Argo CK, Patrie JT, Lackner C, Henry TD, de Lange EE. 203.  et al. 2015. Effects of n-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial. J. Hepatol. 62:190–97 [Google Scholar]
  204. Sanyal AJ, Abdelmalek MF, Suzuki A, Cummings OW, Chojkier M, Group E-AS. 204.  2014. No significant effects of ethyl-eicosapentanoic acid on histologic features of nonalcoholic steatohepatitis in a phase 2 trial. Gastroenterology 147:377–84.e1 [Google Scholar]
  205. Loomba R, Sirlin CB, Ang B, Bettencourt R, Jain R. 205.  et al. (San Diego Integr. NAFLD Res. Consort.). 2015. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology 61:1239–50 [Google Scholar]
  206. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML. 206.  et al. (NASH Clin. Res. Netw.). 2015. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385:956–65 [Google Scholar]
  207. Perry RJ, Zhang D, Zhang XM, Boyer JL, Shulman GI. 207.  2015. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science 347:1253–56 [Google Scholar]
  208. Zein CO, Yerian LM, Gogate P, Lopez R, Kirwan JP. 208.  et al. 2011. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 54:1610–19 [Google Scholar]
  209. Van Wagner LB, Koppe SW, Brunt EM, Gottstein J, Gardikiotes K. 209.  et al. 2011. Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Ann. Hepatol. 10:277–86 [Google Scholar]
  210. Haukeland JW, Damas JK, Konopski Z, Loberg EM, Haaland T. 210.  et al. 2006. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J. Hepatol. 44:1167–74 [Google Scholar]
  211. Baeck C, Wehr A, Karlmark KR, Heymann F, Vucur M. 211.  et al. 2012. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut 61:416–26 [Google Scholar]
  212. Baeck C, Wei X, Bartneck M, Fech V, Heymann F. 212.  et al. 2014. Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C+ macrophage infiltration in mice. Hepatology 59:1060–72 [Google Scholar]
  213. Sanyal A, Ratziu V, Harrison S, Abdelmalek MF, Aithal GP. 213.  et al. 2016. Cenicriviroc versus placebo for the treatment of nonalcoholic steatohepatitis with liver fibrosis: results from the year 1 primary analysis of the phase 2b CENTAUR study. Hepatology 64:1118A [Google Scholar]
  214. Gao X, Zhu Y, Wen Y, Liu G, Wan C. 214.  2016. Efficacy of probiotics in non-alcoholic fatty liver disease in adult and children: a meta-analysis of randomized controlled trials. Hepatol. Res. 46:1226–33 [Google Scholar]
  215. Loomba R, Lawitz E, Mantry PS, Jaya-kumar S, Caldwell SH. 215.  et al. 2016. GS-4997, an inhibitor of apoptosis signal-regulating kinase (ASK1), alone or in combination with simtu-zumab for the treatment of nonalcoholic steatohepatitis (NASH): a randomized, phase 2 trial. Hepatology 64:1119A [Google Scholar]
  216. Anstee QM, Concas D, Kudo H, Levene A, Pollard J. 216.  et al. 2010. Impact of pan-caspase inhibition in animal models of established steatosis and non-alcoholic steatohepatitis. J. Hepatol. 53:542–50 [Google Scholar]
  217. Barreyro FJ, Holod S, Finocchietto PV, Camino AM, Aquino JB. 217.  et al. 2015. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int 35:953–66 [Google Scholar]
  218. Ratziu V, Sheikh MY, Sanyal AJ, Lim JK, Conjeevaram H. 218.  et al. 2012. A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis. Hepatology 55:419–28 [Google Scholar]
  219. Shiffman M, Freilich B, Vuppalanchi R, Watt K, Burgess G. 219.  et al. 2015. LP37: a placebo-controlled, multicenter, double-blind, randomised trial of emricasan in subjects with non-alcoholic fatty liver disease (NAFLD) and raised transaminases. J. Hepatol. 62:S282 [Google Scholar]
  220. Williams CD, Stengel J, Asike MI, Torres DM, Shaw J. 220.  et al. 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 140:124–31 [Google Scholar]
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