Endoplasmic reticulum stress and Oxidative stress in the pathogenesis of Non-alcoholic fatty liver disease

Free Radical Research

Volumn 49, Issue 12, 2015, Pages 1405-1418

  Ashraf, N U ^a,b   Sheikh, T A ^a,b,c  

^a ACADEMY OF SCIENTIFIC AND INNOVATIVE RESEARCH ACSIR   (India)

^b CSIR INDIAN INSTITUTE OF INTEGRATIVE MEDICINE   (India)

^c PK PD and Toxicology Division   (India)

Author keywords

cell death; ER stress; Non alcoholic Fatty liver disease; Oxidative stress

Indexed keywords

ACTIVATING TRANSCRIPTION FACTOR 4; ACTIVATING TRANSCRIPTION FACTOR 6; FAT DROPLET; PROTEIN IRE1; REACTIVE OXYGEN METABOLITE;

APOPTOSIS; BIOSYNTHESIS; DISEASE COURSE; ENDOPLASMIC RETICULUM STRESS; HOMEOSTASIS; HUMAN; INFLAMMATION; INSULIN SYNTHESIS; LIPID METABOLISM; NONALCOHOLIC FATTY LIVER; OXIDATIVE STRESS; PATHOGENESIS; PROTEIN FOLDING; REVIEW; SIGNAL TRANSDUCTION; UNFOLDED PROTEIN RESPONSE; ANIMAL; PATHOPHYSIOLOGY; PHYSIOLOGY;

ANIMALS; ENDOPLASMIC RETICULUM STRESS; HUMANS; NON-ALCOHOLIC FATTY LIVER DISEASE; OXIDATIVE STRESS;

EID: 84946494125     PISSN: 10715762     EISSN: 10292470     Source Type: Journal    
DOI: 10.3109/10715762.2015.1078461     Document Type: Review

References (172)

1. Sahini N, Borlak J. Recent insights into the molecular pathophysiology of lipid droplet formation in hepatocytes. Prog Lipid Res 2014;54:86-112.
2. Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011;141:1249-1253.
3. Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010;51:1972-1978.
4. Schattenberg JM, Schuppan D. Nonalcoholic steatohepatitis: the therapeutic challenge of a global epidemic. Curr Opin Lipidol 2011;22:479-488.
5. Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology 1998;114:842-845.
6. Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 2005;115:2656-2664.
7. Schroder M. Endoplasmic reticulum stress responses. Cell Mol Life Sci 2008;65:862-894.
8. Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal 2007;9:2277-2293.
9. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 2010;140:900-917.
10. Montane J, Cadavez L, Novials A. Stress and the inflammatory process: a major cause of pancreatic cell death in type 2 diabetes. Diabetes Metab Syndr Obes 2014;7:25-34.
11. Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature 2008;454:455-462.
12. Farrukh MR, Nissar UA, Afnan Q, Rafiq RA, Sharma L, Amin S, et al. Oxidative stress mediated Ca(2+) release manifests endoplasmic reticulum stress leading to unfolded protein response in UV-B irradiated human skin cells. J Dermatol Sci 2014;75:24-35.
13. Palomer X, Capdevila-Busquets E, Garreta G, Davidson MM, Vazquez-Carrera M. [PPARalpha attenuates palmitate-induced endoplasmic reticulum stress in human cardiac cells by enhancing AMPK activity.]. Clin Investig Arterioscler 2014.
14. Pagliassotti MJ. Endoplasmic reticulum stress in nonalcoholic fatty liver disease. Annu Rev Nutr 2012;32:17-33.
15. Zhou H, Liu R. ER stress and hepatic lipid metabolism. Front Genet 2014;5:112.
16. Li J, Huang J, Li JS, Chen H, Huang K, Zheng L. Accumulation of endoplasmic reticulum stress and lipogenesis in the liver through generational effects of high fat diets. J Hepatol 2012;56:900-907.
17. Nissar AU, Sharma L, Tasduq SA. Palmitic acid induced lipotoxicity is associated with altered lipid metabolism, enhanced CYP450 2E1 and intracellular calcium mediated ER stress in human hepatoma cells. Toxicology Research 2015.
18. Tariq Z, Green CJ, Hodson L. Are oxidative stress mechanisms the common denominator in the progression from hepatic steatosis towards non-alcoholic steatohepatitis (NASH)? Liver Int 2014.
19. Koek GH, Liedorp PR, Bast A. The role of oxidative stress in non-alcoholic steatohepatitis. Clin Chim Acta 2011;412:1297-1305.
20. Del Ben M, Polimeni L, Carnevale R, Bartimoccia S, Nocella C, Baratta F, et al. NOX2-generated oxidative stress is associated with severity of ultrasound liver steatosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol 2014;14:81.
21. Albano E, Mottaran E, Occhino G, Reale E, Vidali M. Review article: role of oxidative stress in the progression of non-alcoholic steatosis. Aliment Pharmacol Ther 2005;22 Suppl 2:71-73.
22. Zhang XQ, Xu CF, Yu CH, Chen WX, Li YM. Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2014;20:1768-1776.
23. Gentile CL, Frye M, Pagliassotti MJ. Endoplasmic reticulum stress and the unfolded protein response in nonalcoholic fatty liver disease. Antioxid Redox Signal 2011;15:505-521.
24. Gentile CL, Frye MA, Pagliassotti MJ. Fatty acids and the endoplasmic reticulum in nonalcoholic fatty liver disease. Biofactors 2011;37:8-16.
25. Kober L, Zehe C, Bode J. Development of a novel ER stress based selection system for the isolation of highly productive clones. Biotechnol Bioeng 2012;109:2599-2611.
26. Diehl JA, Fuchs SY, Koumenis C. The cell biology of the unfolded protein response. Gastroenterology 2011;141:38-41, 41 e1-2.
27. Bravo R, Parra V, Gatica D, Rodriguez AE, Torrealba N, Paredes F, et al. Endoplasmic reticulum and the unfolded protein response: dynamics and metabolic integration. Int Rev Cell Mol Biol 2013;301:215-290.
28. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011;334:1081-1086.
29. Cullinan SB, Diehl JA. PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress. J Biol Chem 2004;279:20108-20117.
30. Bailey D, O'Hare P. Transmembrane bZIP transcription factors in ER stress signaling and the unfolded protein response. Antioxid Redox Signal 2007;9:2305-2321.
31. Asada R, Kanemoto S, Kondo S, Saito A, Imaizumi K. The signalling from endoplasmic reticulum-resident bZIP transcription factors involved in diverse cellular physiology. J Biochem 2011;149:507-518.
32. Belmont PJ, Chen WJ, Thuerauf DJ, Glembotski CC. Regulation of microRNA expression in the heart by the ATF6 branch of the ER stress response. J Mol Cell Cardiol 2012;52:1176-1182.
33. Pincus D, Chevalier MW, Aragon T, van Anken E, Vidal SE, El-Samad H, Walter P. BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response. PLoS Biol 2010;8:e1000415.
34. Hassler J, Cao SS, Kaufman RJ. IRE1, a double-edged sword in pre-miRNA slicing and cell death. Dev Cell 2012;23:921-923.
35. Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta 2013;1833:3460-3470.
36. Ron D, Hubbard SR. How IRE1 reacts to ER stress. Cell 2008;132:24-26.
37. Deng X, Xiao L, Lang W, Gao F, Ruvolo P, May WS, Jr. Novel role for JNK as a stress-activated Bcl2 kinase. J Biol Chem 2001;276:23681-23688.
38. Lei K, Davis RJ. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci U S A 2003;100:2432-2437.
39. Yamaguchi H, Wang HG. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem 2004;279:45495-45502.
40. Puthalakath H, O'Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 2007;129:1337-1349.
41. Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol 2009;186:323-331.
42. Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 2004;11:381-389.
43. Li G, Mongillo M, Chin KT, Harding H, Ron D, Marks AR, Tabas I. Role of ERO1-alpha-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis. J Cell Biol 2009;186:783-792.
44. Novoa I, Zeng H, Harding HP, Ron D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 2001;153:1011-1022.
45. McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 2001;21:1249-1259.
46. Malhi H, Kaufman RJ. Endoplasmic reticulum stress in liver disease. J Hepatol 2011;54:795-809.
47. Kaplowitz N, Than TA, Shinohara M, Ji C. Endoplasmic reticulum stress and liver injury. Semin Liver Dis 2007;27:367-377.
48. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004;306:457-461.
49. Wang D, Wei Y, Pagliassotti MJ. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 2006;147:943-951.
50. Yang L, Jhaveri R, Huang J, Qi Y, Diehl AM. Endoplasmic reticulum stress, hepatocyte CD1d and NKT cell abnormalities in murine fatty livers. Lab Invest 2007;87:927-937.
51. Sreejayan N, Dong F, Kandadi MR, Yang X, Ren J. Chromium alleviates glucose intolerance, insulin resistance, and hepatic ER stress in obese mice. Obesity (Silver Spring) 2008;16:1331-1337.
52. Rahman SM, Schroeder-Gloeckler JM, Janssen RC, Jiang H, Qadri I, Maclean KN, Friedman JE. CCAAT/enhancing binding protein beta deletion in mice attenuates inflammation, endoplasmic reticulum stress, and lipid accumulation in diet-induced nonalcoholic steatohepatitis. Hepatology 2007;45:1108-1117.
53. Charlton M, Krishnan A, Viker K, Sanderson S, Cazanave S, McConico A, et al. Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol 2011;301:G825-834.
54. Puri P, Mirshahi F, Cheung O, Natarajan R, Maher JW, Kellum JM, Sanyal AJ. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 2008;134:568-576.
55. Gregor MF, Yang L, Fabbrini E, Mohammed BS, Eagon JC, Hotamisligil GS, Klein S. Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes 2009;58:693-700.
56. Eberle D, Hegarty B, Bossard P, Ferre P, Foufelle F. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie 2004;86:839-848.
57. Amemiya-Kudo M, Shimano H, Hasty AH, Yahagi N, Yoshikawa T, Matsuzaka T, et al. Transcriptional activities of nuclear SREBP-1a, -1c, and - 2 to different target promoters of lipogenic and cholesterogenic genes. J Lipid Res 2002;43:1220-1235.
58. Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997;89:331-340.
59. Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, et al. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 2002;110:489-500.
60. Rawson RB. The SREBP pathway-insights from Insigs and insects. Nat Rev Mol Cell Biol 2003;4:631-640.
61. Lee JN, Ye J. Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1. J Biol Chem 2004;279:45257-45265.
62. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002;109:1125-1131.
63. Horton JD, Goldstein JL, Brown MS. SREBPs: transcriptional mediators of lipid homeostasis. Cold Spring Harb Symp Quant Biol 2002;67:491-498.
64. Kammoun HL, Chabanon H, Hainault I, Luquet S, Magnan C, Koike T, et al. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest 2009;119:1201-1215.
65. Engelking LJ, Kuriyama H, Hammer RE, Horton JD, Brown MS, Goldstein JL, Liang G. Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis. J Clin Invest 2004;113:1168-1175.
66. Takaishi K, Duplomb L, Wang MY, Li J, Unger RH. Hepatic insig-1 or - 2 overexpression reduces lipogenesis in obese Zucker diabetic fatty rats and in fasted/refed normal rats. Proc Natl Acad Sci U S A 2004;101:7106-7111.
67. Lee JS, Zheng Z, Mendez R, Ha SW, Xie Y, Zhang K. Pharmacologic ER stress induces non-alcoholic steatohepatitis in an animal model. Toxicol Lett 2012;211:29-38.
68. Dentin R, Girard J, Postic C. Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie 2005;87:81-86.
69. Fu S, Watkins SM, Hotamisligil GS. The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab 2012;15:623-634.
70. Fribley A, Zhang K, Kaufman RJ. Regulation of apoptosis by the unfolded protein response. Methods Mol Biol 2009;559:191-204.
71. Colgan SM, Hashimi AA, Austin RC. Endoplasmic reticulum stress and lipid dysregulation. Expert Rev Mol Med 2011;13:e4.
72. Anderson EK, Hill AA, Hasty AH. Stearic acid accumulation in macrophages induces toll-like receptor 4/2-independent inflammation leading to endoplasmic reticulum stress-mediated apoptosis. Arterioscler Thromb Vasc Biol 2012;32:1687-1695.
73. Zha BS, Wan X, Zhang X, Zha W, Zhou J, Wabitsch M, et al. HIV protease inhibitors disrupt lipid metabolism by activating endoplasmic reticulum stress and inhibiting autophagy activity in adipocytes. PLoS One 2013;8:e59514.
74. Bobrovnikova-Marjon E, Hatzivassiliou G, Grigoriadou C, Romero M, Cavener DR, Thompson CB, Diehl JA. PERK-dependent regulation of lipogenesis during mouse mammary gland development and adipocyte differentiation. Proc Natl Acad Sci U S A 2008;105:16314-16319.
75. Lauressergues E, Bert E, Duriez P, Hum D, Majd Z, Staels B, Cussac D. Does endoplasmic reticulum stress participate in APD-induced hepatic metabolic dysregulation? Neuropharmacology 2012;62:784-796.
76. Oyadomari S, Harding HP, Zhang Y, Oyadomari M, Ron D. Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab 2008;7:520-532.
77. Seo J, Fortuno ES, 3rd, Suh JM, Stenesen D, Tang W, Parks EJ, et al. Atf4 regulates obesity, glucose homeostasis, and energy expenditure. Diabetes 2009;58:2565-2573.
78. Wang C, Huang Z, Du Y, Cheng Y, Chen S, Guo F. ATF4 regulates lipid metabolism and thermogenesis. Cell Res 2010;20:174-184.
79. Xiao G, Zhang T, Yu S, Lee S, Calabuig-Navarro V, Yamauchi J, et al. ATF4 protein deficiency protects against high fructose-induced hypertriglyceridemia in mice. J Biol Chem 2013;288:25350-25361.
80. Li H, Meng Q, Xiao F, Chen S, Du Y, Yu J, et al. ATF4 deficiency protects mice from high-carbohydrate-diet-induced liver steatosis. Biochem J 2011;438:283-289.
81. Ota T, Gayet C, Ginsberg HN. Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents. J Clin Invest 2008;118:316-332.
82. Jo H, Choe SS, Shin KC, Jang H, Lee JH, Seong JK, et al. Endoplasmic reticulum stress induces hepatic steatosis via increased expression of the hepatic very low-density lipoprotein receptor. Hepatology 2013;57:1366-1377.
83. Qiu W, Su Q, Rutledge AC, Zhang J, Adeli K. Glucosamine-induced endoplasmic reticulum stress attenuates apolipoprotein B100 synthesis via PERK signaling. J Lipid Res 2009;50:1814-1823.
84. Zhang K, Wang S, Malhotra J, Hassler JR, Back SH, Wang G, et al. The unfolded protein response transducer IRE1alpha prevents ER stress-induced hepatic steatosis. EMBO J 2011;30:1357-1375.
85. Lee AH, Scapa EF, Cohen DE, Glimcher LH. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 2008;320:1492-1496.
86. Wang S, Chen Z, Lam V, Han J, Hassler J, Finck BN, et al. IRE1alpha-XBP1s induces PDI expression to increase MTP activity for hepatic VLDL assembly and lipid homeostasis. Cell Metab 2012;16:473-486.
87. Jiang S, Yan C, Fang QC, Shao ML, Zhang YL, Liu Y, et al. Fibroblast Growth Factor 21 Is Regulated by the IRE1-alpha-XBP1 Branch of the Unfolded Protein Response and Counteracts ER stress-induced Hepatic Steatosis. J Biol Chem 2014.
88. Wan XS, Lu XH, Xiao YC, Lin Y, Zhu H, Ding T, et al. ATF4- and CHOP-dependent induction of FGF21 through endoplasmic reticulum stress. Biomed Res Int 2014;2014:807874.
89. Sakai J, Nohturfft A, Goldstein JL, Brown MS. Cleavage of sterol regulatory element-binding proteins (SREBPs) at site-1 requires interaction with SREBP cleavage-activating protein. Evidence from in vivo competition studies. J Biol Chem 1998;273:5785-5793.
90. Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 2000;6:1355-1364.
91. Zeng L, Lu M, Mori K, Luo S, Lee AS, Zhu Y, Shyy JY. ATF6 modulates SREBP2-mediated lipogenesis. EMBO J 2004;23:950-958.
92. Yamamoto K, Takahara K, Oyadomari S, Okada T, Sato T, Harada A, Mori K. Induction of liver steatosis and lipid droplet formation in ATF6alpha-knockout mice burdened with pharmacological endoplasmic reticulum stress. Mol Biol Cell 2010;21:2975-2986.
93. Usui M, Yamaguchi S, Tanji Y, Tominaga R, Ishigaki Y, Fukumoto M, et al. Atf6alpha-null mice are glucose intolerant due to pancreatic beta-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance. Metabolism 2012;61:1118-1128.
94. Rutkowski DT, Wu J, Back SH, Callaghan MU, Ferris SP, Iqbal J, et al. UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev Cell 2008;15:829-840.
95. Cinaroglu A, Gao C, Imrie D, Sadler KC. Activating transcription factor 6 plays protective and pathological roles in steatosis due to endoplasmic reticulum stress in zebrafish. Hepatology 2011;54:495-508.
96. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007;8:519-529.
97. Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 2011;13:184-190.
98. Cao J, Dai DL, Yao L, Yu HH, Ning B, Zhang Q, et al. Saturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK/ATF4/CHOP signaling pathway. Mol Cell Biochem 2012;364:115-129.
99. Tamaki N, Hatano E, Taura K, Tada M, Kodama Y, Nitta T, et al. CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury. Am J Physiol Gastrointest Liver Physiol 2008;294:G498-505.
100. Toriguchi K, Hatano E, Tanabe K, Takemoto K, Nakamura K, Koyama Y, et al. Attenuation of steatohepatitis, fibrosis, and carcinogenesis in mice fed a methionine-choline deficient diet by CCAAT/enhancer-binding protein homologous protein deficiency. J Gastroenterol Hepatol 2014;29:1109-1118.
101. DeZwaan-McCabe D, Riordan JD, Arensdorf AM, Icardi MS, Dupuy AJ, Rutkowski DT. The stress-regulated transcription factor CHOP promotes hepatic inflammatory gene expression, fibrosis, and oncogenesis. PLoS Genet 2013;9:e1003937.
102. Gu X, Li K, Laybutt DR, He ML, Zhao HL, Chan JC, Xu G. Bip overexpression, but not CHOP inhibition, attenuates fatty-acid-induced endoplasmic reticulum stress and apoptosis in HepG2 liver cells. Life Sci 2010;87:724-732.
103. Suyama K, Watanabe M, Sakabe K, Otomo A, Okada Y, Terayama H, et al. GRP78 suppresses lipid peroxidation and promotes cellular antioxidant levels in glial cells following hydrogen peroxide exposure. PLoS One 2014;9:e86951.
104. Negre-Salvayre A, Auge N, Ayala V, Basaga H, Boada J, Brenke R, et al. Pathological aspects of lipid peroxidation. Free Radic Res 2010;44:1125-1171.
105. Sumida Y, Niki E, Naito Y, Yoshikawa T. Involvement of free radicals and oxidative stress in NAFLD/NASH. Free Radic Res 2013;47:869-880.
106. Anderson N, Borlak J. Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacol Rev 2008;60:311-357.
107. Videla LA, Rodrigo R, Orellana M, Fernandez V, Tapia G, Quinones L, et al. Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients. Clin Sci (Lond) 2004;106:261-268.
108. Erhardt A, Stahl W, Sies H, Lirussi F, Donner A, Haussinger D. Plasma levels of vitamin E and carotenoids are decreased in patients with Nonalcoholic Steatohepatitis (NASH). Eur J Med Res 2011;16:76-78.
109. Liu S, Shi W, Li G, Jin B, Chen Y, Hu H, et al. Plasma reactive carbonyl species levels and risk of non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2011;26:1010-1015.
110. Rolo AP, Teodoro JS, Palmeira CM. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic Biol Med 2012;52:59-69.
111. Zein CO, Lopez R, Fu X, Kirwan JP, Yerian LM, McCullough AJ, et al. Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: new evidence on the potential therapeutic mechanism. Hepatology 2012;56:1291-1299.
112. Matsuzawa N, Takamura T, Kurita S, Misu H, Ota T, Ando H, et al. Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology 2007;46:1392-1403.
113. Niki E. Lipid peroxidation: physiological levels and dual biological effects. Free Radic Biol Med 2009;47:469-484.
114. Davies MJ. Myeloperoxidase-derived oxidation: mechanisms of biological damage and its prevention. J Clin Biochem Nutr 2011;48:8-19.
115. Caldwell SH, Swerdlow RH, Khan EM, Iezzoni JC, Hespenheide EE, Parks JK, Parker WD, Jr. Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepatol 1999;31:430-434.
116. Hennig EE, Mikula M, Goryca K, Paziewska A, Ledwon J, Nesteruk M, et al. Extracellular matrix and cytochrome P450 gene expression can distinguish steatohepatitis from steatosis in mice. J Cell Mol Med 2014.
117. Leung T, Rajendran R, Singh S, Garva R, Krstic-Demonacos M, Demonacos C. Cytochrome P450 2E1 (CYP2E1) regulates the response to oxidative stress and migration of breast cancer cells. Breast Cancer Res 2013;15:R107.
118. Lieber CS. Cytochrome P-4502E1: its physiological and pathological role. Physiol Rev 1997;77:517-544.
119. Aubert J, Begriche K, Knockaert L, Robin MA, Fromenty B. Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role. Clin Res Hepatol Gastroenterol 2011;35:630-637.
120. Begriche K, Igoudjil A, Pessayre D, Fromenty B. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion 2006;6:1-28.
121. Robertson G, Leclercq I, Farrell GC. Nonalcoholic steatosis and steatohepatitis. II. Cytochrome P-450 enzymes and oxidative stress. Am J Physiol Gastrointest Liver Physiol 2001;281:G1135-1139.
122. Mari M, Caballero F, Colell A, Morales A, Caballeria J, Fernandez A, et al. Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metab 2006;4:185-198.
123. Woodcroft KJ, Novak RF. The role of phosphatidylinositol 3-kinase, Src kinase, and protein kinase A signaling pathways in insulin and glucagon regulation of CYP2E1 expression. Biochem Biophys Res Commun 1999;266:304-307.
124. Jiang JX, Török NJ. NADPH Oxidases in Chronic Liver Diseases. Advances in Hepatology 2014;2014.
125. Paik YH, Kim J, Aoyama T, De Minicis S, Bataller R, Brenner DA. Role of NADPH oxidases in liver fibrosis. Antioxid Redox Signal 2014;20:2854-2872.
126. Guichard C, Moreau R, Pessayre D, Epperson TK, Krause KH. NOX family NADPH oxidases in liver and in pancreatic islets: a role in the metabolic syndrome and diabetes? Biochem Soc Trans 2008;36:920-929.
127. Carmiel-Haggai M, Cederbaum AI, Nieto N. A high-fat diet leads to the progression of non-alcoholic fatty liver disease in obese rats. FASEB J 2005;19:136-138.
128. De Minicis S, Seki E, Paik YH, Osterreicher CH, Kodama Y, Kluwe J, et al. Role and cellular source of nicotinamide adenine dinucleotide phosphate oxidase in hepatic fibrosis. Hepatology 2010;52:1420-1430.
129. Liu Q, Li H, Wang N, Chen H, Jin Q, Zhang R, et al. Polymorphism of rs1836882 in NOX4 gene modifies associations between dietary caloric intake and ROS levels in peripheral blood mononuclear cells. PLoS One 2013;8:e85660.
130. Li Y, Mouche S, Sajic T, Veyrat-Durebex C, Supale R, Pierroz D, et al. Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity. Int J Obes (Lond) 2012;36:1503-1513.
131. Laurindo FR, Araujo TL, Abrahao TB. Nox NADPH oxidases and the endoplasmic reticulum. Antioxid Redox Signal 2014;20:2755-2775.
132. Santos CX, Tanaka LY, Wosniak J, Laurindo FR. Mechanisms and implications of reactive oxygen species generation during the unfolded protein response: roles of endoplasmic reticulum oxidoreductases, mitochondrial electron transport, and NADPH oxidase. Antioxid Redox Signal 2009;11:2409-2427.
133. Creighton TE, Hillson DA, Freedman RB. Catalysis by protein-disulphide isomerase of the unfolding and refolding of proteins with disulphide bonds. J Mol Biol 1980;142:43-62.
134. Pollard MG, Travers KJ, Weissman JS. Ero1p: a novel and ubiquitous protein with an essential role in oxidative protein folding in the endoplasmic reticulum. Mol Cell 1998;1:171-182.
135. Tu BP, Weissman JS. Oxidative protein folding in eukaryotes: mechanisms and consequences. J Cell Biol 2004;164:341-346.
136. Cao SS, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid Redox Signal 2014;21:396-413.
137. Higa A, Chevet E. Redox signaling loops in the unfolded protein response. Cell Signal 2012;24:1548-1555.
138. Nseir W, Hellou E, Assy N. Role of diet and lifestyle changes in nonalcoholic fatty liver disease. World J Gastroenterol 2014;20:9338-9344.
139. Fan JG, Cao HX. Role of diet and nutritional management in non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2013;28 Suppl 4:81-87.
140. Akyuz F, Demir K, Ozdil S, Aksoy N, Poturoglu S, Ibrisim D, et al. The effects of rosiglitazone, metformin, and diet with exercise in nonalcoholic fatty liver disease. Dig Dis Sci 2007;52:2359-2367.
141. Oh S, Tanaka K, Tsujimoto T, So R, Shida T, Shoda J. Regular exercise coupled to diet regimen accelerates reduction of hepatic steatosis and associated pathological conditions in nonalcoholic fatty liver disease. Metab Syndr Relat Disord 2014;12:290-298.
142. Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A, Serfaty L, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 2008;135:100-110.
143. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675-1685.
144. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006;355:2297-2307.
145. Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008;135:1176-1184.
146. Lomonaco R, Sunny NE, Bril F, Cusi K. Nonalcoholic fatty liver disease: current issues and novel treatment approaches. Drugs 2013;73:1-14.
147. Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, Diehl AM. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med 2000;6:998-1003.
148. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet 2001;358:893-894.
149. Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 2005;100:1082-1090.
150. Haukeland JW, Konopski Z, Eggesbo HB, von Volkmann HL, Raschpichler G, Bjoro K, Haaland T, et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 2009;44:853-860.
151. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011;305:1659-1668.
152. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012;142:1592-1609.
153. Gomez-Dominguez E, Gisbert JP, Moreno-Monteagudo JA, Garcia-Buey L, Moreno-Otero R. A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients. Aliment Pharmacol Ther 2006;23:1643-1647.
154. Hyogo H, Tazuma S, Arihiro K, Iwamoto K, Nabeshima Y, Inoue M, et al. Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia. Metabolism 2008;57:1711-1718.
155. Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: A randomized placebo-controlled trial. J Clin Gastroenterol 2009;43:990-994.
156. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. 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 2012;55:2005-2023.
157. Yoneda M, Fujita K, Nozaki Y, Endo H, Takahashi H, Hosono K, et al. Efficacy of ezetimibe for the treatment of non-alcoholic steatohepatitis: An open-label, pilot study. Hepatol Res 2010;40:566-573.
158. Adams LA, Zein CO, Angulo P, Lindor KD. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol 2004;99:2365-2368.
159. Satapathy SK, Sakhuja P, Malhotra V, Sharma BC, Sarin SK. Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis and necroinflammation in patients with non-alcoholic steatohepatitis. J Gastroenterol Hepatol 2007;22:634-638.
160. Van Wagner LB, Koppe SW, Brunt EM, Gottstein J, Gardikiotes K, Green RM, Rinella ME. Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Ann Hepatol 2011;10:277-286.
161. Takahashi Y, Sugimoto K, Inui H, Fukusato T. Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol 2015;21:3777-3785.
162. Svegliati-Baroni G, Candelaresi C, Saccomanno S, Ferretti G, Bachetti T, Marzioni M, et al. A model of insulin resistance and nonalcoholic steatohepatitis in rats: role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury. Am J Pathol 2006;169:846-860.
163. Capanni M, Calella F, Biagini MR, Genise S, Raimondi L, Bedogni G, et al. Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study. Aliment Pharmacol Ther 2006;23:1143-1151.
164. Tanaka N, Sano K, Horiuchi A, Tanaka E, Kiyosawa K, Aoyama T. Highly purified eicosapentaenoic acid treatment improves nonalcoholic steatohepatitis. J Clin Gastroenterol 2008;42:413-418.
165. Herrera E, Barbas C. Vitamin E: action, metabolism and perspectives. J Physiol Biochem 2001;57:43-56.
166. Lavine JE. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr 2000;136:734-738.
167. Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2003;98:2485-2490.
168. Miller ER, 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46.
169. Klein EA, Thompson IM, Jr., Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011;306:1549-1556.
170. Catalgol B, Batirel S, Taga Y, Ozer NK. Resveratrol: French paradox revisited. Front Pharmacol 2012;3:141.
171. Shang J, Chen LL, Xiao FX, Sun H, Ding HC, Xiao H. Resveratrol improves non-alcoholic fatty liver disease by activating AMP-activated protein kinase. Acta Pharmacol Sin 2008;29:698-706.
172. Bujanda L, Hijona E, Larzabal M, Beraza M, Aldazabal P, Garcia-Urkia N, et al. Resveratrol inhibits nonalcoholic fatty liver disease in rats. BMC Gastroenterol 2008;8:40.