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Oxidative Stress in Nonalcoholic Fatty Liver Disease

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Studies on Hepatic Disorders

Abstract

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent cause of liver disease in Western countries and represents a spectrum of diseases ranging from simple steatosis through steatohepatitis (NASH) and fibrosis, which can further progress to cirrhosis and hepatocellular carcinoma. While fatty liver is a benign condition, and triglyceride accumulation actually serves as “sink” or protective pathway in lipid metabolism, a growing body of evidence suggests that the type rather than the quantity of lipids accumulating may play a central role in disease progression. In fact, lipids such as free fatty acids and cholesterol, among others, have been associated to lipotoxicity, oxidative stress, and mitochondrial dysfunction. Oxidative stress, characterized by an imbalance between pro- and antioxidant mechanisms, followed by mitochondrial dysfunction are thought to play a key role in the pathogenesis of NAFLD. Different sources of oxidative stress coexists in hepatocytes especially those derived from mitochondrial, microsomal, peroxisomal, and lysosomal origin, many of them linked to FFA metabolism, as we will discuss in detail.

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References

  1. Abdelmalek MF, Diehl AM (2007) Nonalcoholic fatty liver disease as a complication of insulin resistance. Med Clin North Am 91(6):1125–1149. doi:10.1016/j.mcna.2007.06.001, ix

    CAS  PubMed  Google Scholar 

  2. Adams LA, Lindor KD (2007) Nonalcoholic fatty liver disease. Ann Epidemiol 17(11):863–869. doi:10.1016/j.annepidem.2007.05.013

    PubMed  Google Scholar 

  3. 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(1):113–121

    PubMed  Google Scholar 

  4. Alkhouri N, Berk M, Yerian L, Lopez R, Chung YM, Zhang R, McIntyre TM, Feldstein AE, Hazen SL (2014) OxNASH score correlates with Histologic features and severity of nonalcoholic fatty liver disease. Dig Dis Sci 59(7):1617–1624. doi:10.1007/s10620-014-3031-8

    PubMed Central  CAS  PubMed  Google Scholar 

  5. Alkhouri N, Dixon LJ, Feldstein AE (2009) Lipotoxicity in nonalcoholic fatty liver disease: not all lipids are created equal. Expert Rev Gastroenterol Hepatol 3(4):445–451. doi:10.1586/egh.09.32

    PubMed Central  CAS  PubMed  Google Scholar 

  6. Aller R, de Luis DA, Fernandez L, Calle F, Velayos B, Olcoz JL, Izaola O, Sagrado MG, Conde R, Gonzalez JM (2008) Influence of insulin resistance and adipokines in the grade of steatosis of nonalcoholic fatty liver disease. Dig Dis Sci 53(4):1088–1092. doi:10.1007/s10620-007-9981-3

    CAS  PubMed  Google Scholar 

  7. Anania FA (2005) Adiponectin and alcoholic fatty liver: is it, after all, about what you eat? Hepatology 42(3):530–532. doi:10.1002/hep.20861

    PubMed  Google Scholar 

  8. Aoyama T, Peters JM, Iritani N, Nakajima T, Furihata K, Hashimoto T, Gonzalez FJ (1998) Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem 273(10):5678–5684

    CAS  PubMed  Google Scholar 

  9. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y (2012) Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. 1999. Biochem Biophys Res Commun 425(3):560–564. doi:10.1016/j.bbrc.2012.08.024

    CAS  PubMed  Google Scholar 

  10. Aubert J, Begriche K, Knockaert L, Robin MA, Fromenty B (2011) Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role. Clin Res Hepatol Gastroenterol 35(10):630–637. doi:10.1016/j.clinre.2011.04.015

    CAS  PubMed  Google Scholar 

  11. Bidlack WR, Brown RC, Mohan C (1986) Nutritional parameters that alter hepatic drug metabolism, conjugation, and toxicity. Fed Proc 45(2):142–148

    CAS  PubMed  Google Scholar 

  12. Blindenbacher A, Wang X, Langer I, Savino R, Terracciano L, Heim MH (2003) Interleukin 6 is important for survival after partial hepatectomy in mice. Hepatology 38(3):674–682. doi:10.1053/jhep.2003.50378

    CAS  PubMed  Google Scholar 

  13. Bogenhagen DF (1999) Repair of mtDNA in vertebrates. Am J Hum Genet 64(5):1276–1281. doi:10.1086/302392

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Brun P, Castagliuolo I, Di Leo V, Buda A, Pinzani M, Palu G, Martines D (2007) Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 292(2):G518–G525. doi:10.1152/ajpgi.00024.2006

    CAS  PubMed  Google Scholar 

  15. 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(4):634–642. doi:10.1007/s00125-005-1682-x

    CAS  PubMed  Google Scholar 

  16. Caballero F, Fernandez A, De Lacy AM, Fernandez-Checa JC, Caballeria J, Garcia-Ruiz C (2009) Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH. J Hepatol 50(4):789–796. doi:10.1016/j.jhep.2008.12.016

    CAS  PubMed  Google Scholar 

  17. 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(3):430–434

    CAS  PubMed  Google Scholar 

  18. 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(17):1659–1664

    CAS  PubMed  Google Scholar 

  19. Cressman DE, Greenbaum LE, DeAngelis RA, Ciliberto G, Furth EE, Poli V, Taub R (1996) Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 274(5291):1379–1383

    CAS  PubMed  Google Scholar 

  20. Csak T, Velayudham A, Hritz I, Petrasek J, Levin I, Lippai D, Catalano D, Mandrekar P, Dolganiuc A, Kurt-Jones E, Szabo G (2011) Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice. Am J Physiol Gastrointest Liver Physiol 300(3):G433–G441. doi:10.1152/ajpgi.00163.2009

    PubMed Central  PubMed  Google Scholar 

  21. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ, American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association (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. Am J Gastroenterol 107(6):811–826. doi:10.1038/ajg.2012.128

    PubMed  Google Scholar 

  22. Chavin KD, Yang S, Lin HZ, Chatham J, Chacko VP, Hoek JB, Walajtys-Rode E, Rashid A, Chen CH, Huang CC, Wu TC, Lane MD, Diehl AM (1999) Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion. J Biol Chem 274(9):5692–5700

    CAS  PubMed  Google Scholar 

  23. Chen G, Liang G, Ou J, Goldstein JL, Brown MS (2004) Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver. Proc Natl Acad Sci U S A 101(31):11245–11250. doi:10.1073/pnas.0404297101

    PubMed Central  CAS  PubMed  Google Scholar 

  24. Cheung O, Sanyal AJ (2008) Abnormalities of lipid metabolism in nonalcoholic fatty liver disease. Semin Liver Dis 28(4):351–359. doi:10.1055/s-0028-1091979

    CAS  PubMed  Google Scholar 

  25. Choi SH, Ginsberg HN (2011) Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance. Trends Endocrinol Metab 22(9):353–363. doi:10.1016/j.tem.2011.04.007

    PubMed Central  PubMed  Google Scholar 

  26. Choi SS, Diehl AM (2008) Hepatic triglyceride synthesis and nonalcoholic fatty liver disease. Curr Opin Lipidol 19(3):295–300. doi:10.1097/MOL.0b013e3282ff5e55

    CAS  PubMed  Google Scholar 

  27. Day CP (2002) Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol 16(5):663–678

    CAS  PubMed  Google Scholar 

  28. Day CP (2006) From fat to inflammation. Gastroenterology 130(1):207–210. doi:10.1053/j.gastro.2005.11.017

    CAS  PubMed  Google Scholar 

  29. Day CP, James OF (1998) Steatohepatitis: a tale of two “hits”? Gastroenterology 114(4):842–845

    CAS  PubMed  Google Scholar 

  30. de Almeida IT, Cortez-Pinto H, Fidalgo G, Rodrigues D, Camilo ME (2002) Plasma total and free fatty acids composition in human non-alcoholic steatohepatitis. Clin Nutr 21(3):219–223

    PubMed  Google Scholar 

  31. Dentin R, Benhamed F, Hainault I, Fauveau V, Foufelle F, Dyck JR, Girard J, Postic C (2006) Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice. Diabetes 55(8):2159–2170. doi:10.2337/db06-0200

    CAS  PubMed  Google Scholar 

  32. Dey A, Cederbaum AI (2007) Induction of cytochrome P450 2E1 [corrected] promotes liver injury in ob/ob mice. Hepatology 45(6):1355–1365. doi:10.1002/hep.21603

    CAS  PubMed  Google Scholar 

  33. 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(5):1343–1351. doi:10.1172/JCI23621

    PubMed Central  CAS  PubMed  Google Scholar 

  34. Dowman JK, Tomlinson JW, Newsome PN (2010) Pathogenesis of non-alcoholic fatty liver disease. QJM 103(2):71–83. doi:10.1093/qjmed/hcp158

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Drose S, Brandt U, Wittig I (2014) Mitochondrial respiratory chain complexes as sources and targets of thiol-based redox-regulation. Biochim Biophys Acta 1844(8):1344–1354. doi:10.1016/j.bbapap.2014.02.006

    PubMed  Google Scholar 

  36. Eaton S, Bartlett K, Pourfarzam M (1996) Mammalian mitochondrial beta-oxidation. Biochem J 320(Pt 2):345–357

    PubMed Central  CAS  PubMed  Google Scholar 

  37. Eguchi Y, Hyogo H, Ono M, Mizuta T, Ono N, Fujimoto K, Chayama K, Saibara T, Jsg N (2012) Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2009 to 2010 in Japan: a multicenter large retrospective study. J Gastroenterol 47(5):586–595. doi:10.1007/s00535-012-0533-z

    CAS  PubMed  Google Scholar 

  38. El-Assal O, Hong F, Kim WH, Radaeva S, Gao B (2004) IL-6-deficient mice are susceptible to ethanol-induced hepatic steatosis: IL-6 protects against ethanol-induced oxidative stress and mitochondrial permeability transition in the liver. Cell Mol Immunol 1(3):205–211

    CAS  PubMed  Google Scholar 

  39. Endo M, Masaki T, Seike M, Yoshimatsu H (2007) TNF-alpha induces hepatic steatosis in mice by enhancing gene expression of sterol regulatory element binding protein-1c (SREBP-1c). Exp Biol Med 232(5):614–621

    CAS  Google Scholar 

  40. Ertle J, Dechene A, Sowa JP, Penndorf V, Herzer K, Kaiser G, Schlaak JF, Gerken G, Syn WK, Canbay A (2011) Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int J Cancer 128(10):2436–2443. doi:10.1002/ijc.25797

    CAS  PubMed  Google Scholar 

  41. 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 U S A 106(36):15430–15435. doi:10.1073/pnas.0904944106

    PubMed Central  CAS  PubMed  Google Scholar 

  42. Fahimi HD, Reinicke A, Sujatta M, Yokota S, Ozel M, Hartig F, Stegmeier K (1982) The short- and long-term effects of bezafibrate in the rat. Ann N Y Acad Sci 386:111–135

    CAS  PubMed  Google Scholar 

  43. Farhadi A, Gundlapalli S, Shaikh M, Frantzides C, Harrell L, Kwasny MM, Keshavarzian A (2008) Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis. Liver Int 28(7):1026–1033. doi:10.1111/j.1478-3231.2008.01723.x

    PubMed Central  PubMed  Google Scholar 

  44. 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(2):437–443

    PubMed  Google Scholar 

  45. Feldstein AE, Lopez R, Tamimi TA, Yerian L, Chung YM, Berk M, Zhang R, McIntyre TM, Hazen SL (2010) Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Lipid Res 51(10):3046–3054. doi:10.1194/jlr.M007096

    PubMed Central  CAS  PubMed  Google Scholar 

  46. Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, Burgart LJ, Gores GJ (2004) Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 40(1):185–194. doi:10.1002/hep.20283

    CAS  PubMed  Google Scholar 

  47. Feldstein AE, Werneburg NW, Li Z, Bronk SF, Gores GJ (2006) Bax inhibition protects against free fatty acid-induced lysosomal permeabilization. Am J Physiol Gastrointest Liver Physiol 290(6):G1339–G1346. doi:10.1152/ajpgi.00509.2005

    PubMed Central  CAS  PubMed  Google Scholar 

  48. Fernandez A, Colell A, Caballero F, Matias N, Garcia-Ruiz C, Fernandez-Checa JC (2009) Mitochondrial S-adenosyl-L-methionine transport is insensitive to alcohol-mediated changes in membrane dynamics. Alcohol Clin Exp Res 33(7):1169–1180. doi:10.1111/ j.1530-0277.2009.00940.x

  49. Gaggini M, Morelli M, Buzzigoli E, DeFronzo RA, Bugianesi E, Gastaldelli A (2013) Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients 5(5):1544–1560. doi:10.3390/nu5051544

    PubMed Central  CAS  PubMed  Google Scholar 

  50. Gambino R, Musso G, Cassader M (2011) Redox balance in the pathogenesis of nonalcoholic fatty liver disease: mechanisms and therapeutic opportunities. Antioxid Redox Signal 15(5):1325–1365. doi:10.1089/ars.2009.3058

    CAS  PubMed  Google Scholar 

  51. Garcia-Ruiz C, Colell A, Mari M, Morales A, Calvo M, Enrich C, Fernandez-Checa JC (2003) Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice. J Clin Invest 111(2):197–208. doi:10.1172/JCI16010

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Garcia-Ruiz C, Colell A, Mari M, Morales A, Fernandez-Checa JC (1997) Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species. Role of mitochondrial glutathione. J Biol Chem 272(17):11369–11377

    CAS  PubMed  Google Scholar 

  53. Garcia-Ruiz C, Fernandez-Checa JC (2006) Mitochondrial glutathione: hepatocellular survival-death switch. J Gastroenterol Hepatol 21(Suppl 3):S3–S6. doi:10.1111/j.1440-1746.2006.04570.x

    CAS  PubMed  Google Scholar 

  54. Goldfischer SL (1988) Peroxisomal diseases. Prog Clin Biol Res 282:117–137

    CAS  PubMed  Google Scholar 

  55. Grattagliano I, de Bari O, Bernardo TC, Oliveira PJ, Wang DQ, Portincasa P (2012) Role of mitochondria in nonalcoholic fatty liver disease–from origin to propagation. Clin Biochem 45(9):610–618. doi:10.1016/j.clinbiochem.2012.03.024

    CAS  PubMed  Google Scholar 

  56. Guicciardi ME, Leist M, Gores GJ (2004) Lysosomes in cell death. Oncogene 23(16):2881–2890. doi:10.1038/sj.onc.1207512

    CAS  PubMed  Google Scholar 

  57. Halestrap AP, Woodfield KY, Connern CP (1997) Oxidative stress, thiol reagents, and membrane potential modulate the mitochondrial permeability transition by affecting nucleotide binding to the adenine nucleotide translocase. J Biol Chem 272(6):3346–3354

    CAS  PubMed  Google Scholar 

  58. Handa P, Maliken BD, Nelson JE, Morgan-Stevenson V, Messner DJ, Dhillon BK, Klintworth HM, Beauchamp M, Yeh MM, Elfers CT, Roth CL, Kowdley KV (2013) Reduced adiponectin signaling due to weight gain results in nonalcoholic steatohepatitis through impaired mitochondrial biogenesis. Hepatology. doi:10.1002/hep.26946

    Google Scholar 

  59. Hardwick JP (2008) Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases. Biochem Pharmacol 75(12):2263–2275. doi:10.1016/j.bcp.2008.03.004

    CAS  PubMed  Google Scholar 

  60. Hermesh O, Kalderon B, Bar-Tana J (1998) Mitochondria uncoupling by a long chain fatty acyl analogue. J Biol Chem 273(7):3937–3942

    CAS  PubMed  Google Scholar 

  61. Hiltunen JK, Karki T, Hassinen IE, Osmundsen H (1986) beta-Oxidation of polyunsaturated fatty acids by rat liver peroxisomes. A role for 2,4-dienoyl-coenzyme A reductase in peroxisomal beta-oxidation. J Biol Chem 261(35):16484–16493

    CAS  PubMed  Google Scholar 

  62. Hotamisligil GS, Spiegelman BM (1994) Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes 43(11):1271–1278

    CAS  PubMed  Google Scholar 

  63. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y (2000) Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20(6):1595–1599

    CAS  PubMed  Google Scholar 

  64. 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(4):595–604

    CAS  PubMed  Google Scholar 

  65. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J (2004) Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 40(1):46–54. doi:10.1002/hep.20280

    CAS  PubMed  Google Scholar 

  66. Hurd TR, Prime TA, Harbour ME, Lilley KS, Murphy MP (2007) Detection of reactive oxygen species-sensitive thiol proteins by redox difference gel electrophoresis: implications for mitochondrial redox signaling. J Biol Chem 282(30):22040–22051. doi:10.1074/jbc.M703591200

    CAS  PubMed  Google Scholar 

  67. Hussain MM, Shi J, Dreizen P (2003) Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res 44(1):22–32

    CAS  PubMed  Google Scholar 

  68. Hwang JH, Stein DT, Barzilai N, Cui MH, Tonelli J, Kishore P, Hawkins M (2007) Increased intrahepatic triglyceride is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy studies. Am J Physiol Endocrinol Metab 293(6):E1663–E1669. doi:10.1152/ajpendo.00590.2006

    CAS  PubMed  Google Scholar 

  69. Ibrahim SH, Kohli R, Gores GJ (2011) Mechanisms of lipotoxicity in NAFLD and clinical implications. J Pediatr Gastroenterol Nutr 53(2):131–140. doi:10.1097/MPG.0b013e31822578db

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Jaeschke H (2011) Reactive oxygen and mechanisms of inflammatory liver injury: present concepts. J Gastroenterol Hepatol 26(Suppl 1):173–179. doi:10.1111/j.1440-1746.2010.06592.x

    CAS  PubMed  Google Scholar 

  71. Jin X, Zimmers TA, Perez EA, Pierce RH, Zhang Z, Koniaris LG (2006) Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair. Hepatology 43(3):474–484. doi:10.1002/hep.21087

    CAS  PubMed  Google Scholar 

  72. Johansson AC, Appelqvist H, Nilsson C, Kagedal K, Roberg K, Ollinger K (2010) Regulation of apoptosis-associated lysosomal membrane permeabilization. Apoptosis 15(5):527–540. doi:10.1007/s10495-009-0452-5

    PubMed Central  CAS  PubMed  Google Scholar 

  73. Kagan VE, Tyurin VA, Jiang J, Tyurina YY, Ritov VB, Amoscato AA, Osipov AN, Belikova NA, Kapralov AA, Kini V, Vlasova II, Zhao Q, Zou M, Di P, Svistunenko DA, Kurnikov IV, Borisenko GG (2005) Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors. Nat Chem Biol 1(4):223–232. doi:10.1038/nchembio727

    CAS  PubMed  Google Scholar 

  74. Kaser S, Moschen A, Cayon A, Kaser A, Crespo J, Pons-Romero F, Ebenbichler CF, Patsch JR, Tilg H (2005) Adiponectin and its receptors in non-alcoholic steatohepatitis. Gut 54(1):117–121. doi:10.1136/gut.2003.037010

    PubMed Central  CAS  PubMed  Google Scholar 

  75. Kawano Y, Cohen DE (2013) Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J Gastroenterol 48(4):434–441. doi:10.1007/s00535-013-0758-5

    PubMed Central  CAS  PubMed  Google Scholar 

  76. Kim CH, Younossi ZM (2008) Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome. Cleve Clin J Med 75(10):721–728

    PubMed  Google Scholar 

  77. Koek GH, Liedorp PR, Bast A (2011) The role of oxidative stress in non-alcoholic steatohepatitis. Clin chim Acta 412(15–16):1297–1305. doi:10.1016/j.cca.2011.04.013

    CAS  PubMed  Google Scholar 

  78. Kohjima M, Enjoji M, Higuchi N, Kato M, Kotoh K, Yoshimoto T, Fujino T, Yada M, Yada R, Harada N, Takayanagi R, Nakamuta M (2007) Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. Int J Mol Med 20(3):351–358

    CAS  PubMed  Google Scholar 

  79. Kohli R, Pan X, Malladi P, Wainwright MS, Whitington PF (2007) Mitochondrial reactive oxygen species signal hepatocyte steatosis by regulating the phosphatidylinositol 3-kinase cell survival pathway. J Biol Chem 282(29):21327–21336. doi:10.1074/jbc.M701759200

    CAS  PubMed  Google Scholar 

  80. Koo SH (2013) Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis. Clin Mol Hepatol 19(3):210–215. doi:10.3350/cmh.2013.19.3.210

    PubMed Central  PubMed  Google Scholar 

  81. Lazo M, Clark JM (2008) The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis 28(4):339–350. doi:10.1055/s-0028-1091978

    PubMed  Google Scholar 

  82. Leung AW, Halestrap AP (2008) Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta 1777(7–8):946–952. doi:10.1016/j.bbabio.2008.03.009

    CAS  PubMed  Google Scholar 

  83. Leung TM, Nieto N (2013) CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease. J Hepatol 58(2):395–398. doi:10.1016/j.jhep.2012.08.018

    CAS  PubMed  Google Scholar 

  84. Li Z, Berk M, McIntyre TM, Gores GJ, Feldstein AE (2008) The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity. Hepatology 47(5):1495–1503. doi:10.1002/hep.22183

    PubMed Central  CAS  PubMed  Google Scholar 

  85. Li ZZ, Berk M, McIntyre TM, Feldstein AE (2009) Hepatic lipid partitioning and liver damage in nonalcoholic fatty liver disease: role of stearoyl-CoA desaturase. J Biol Chem 284(9):5637–5644. doi:10.1074/jbc.M807616200

    PubMed Central  CAS  PubMed  Google Scholar 

  86. 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 U S A 100(6):3077–3082. doi:10.1073/pnas.0630588100

    PubMed Central  CAS  PubMed  Google Scholar 

  87. Lonardo A, Lombardini S, Ricchi M, Scaglioni F, Loria P (2005) Review article: hepatic steatosis and insulin resistance. Aliment Pharmacol Ther 22(Suppl 2):64–70. doi:10.1111/ j.1365-2036.2005.02600.x

  88. Loomba R, Abraham M, Unalp A, Wilson L, Lavine J, Doo E, Bass NM, Nonalcoholic Steatohepatitis Clinical Research N (2012) Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 56(3):943–951. doi:10.1002/hep.25772

    PubMed Central  PubMed  Google Scholar 

  89. Loomba R, Sanyal AJ (2013) The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 10(11):686–690. doi:10.1038/nrgastro.2013.171

    CAS  PubMed  Google Scholar 

  90. Machado MV, Ferreira DM, Castro RE, Silvestre AR, Evangelista T, Coutinho J, Carepa F, Costa A, Rodrigues CM, Cortez-Pinto H (2012) Liver and muscle in morbid obesity: the interplay of fatty liver and insulin resistance. PLoS One 7(2):e31738. doi:10.1371/journal.pone.0031738

    PubMed Central  CAS  PubMed  Google Scholar 

  91. Malhi H, Bronk SF, Werneburg NW, Gores GJ (2006) Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem 281(17):12093–12101. doi:10.1074/jbc.M510660200

    CAS  PubMed  Google Scholar 

  92. Malhi H, Gores GJ (2008) Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis 28(4):360–369. doi:10.1055/s-0028-1091980

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, Vanni E, Villanova N, Melchionda N, Rizzetto M (2003) Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37(4):917–923. doi:10.1053/jhep.2003.50161

    PubMed  Google Scholar 

  94. Mari M, Caballero F, Colell A, Morales A, Caballeria J, Fernandez A, Enrich C, Fernandez-Checa JC, Garcia-Ruiz C (2006) Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metab 4(3):185–198. doi:10.1016/j.cmet.2006.07.006

    CAS  PubMed  Google Scholar 

  95. Mari M, Colell A, Morales A, Caballero F, Moles A, Fernandez A, Terrones O, Basanez G, Antonsson B, Garcia-Ruiz C, Fernandez-Checa JC (2008) Mechanism of mitochondrial glutathione-dependent hepatocellular susceptibility to TNF despite NF-kappaB activation. Gastroenterology 134(5):1507–1520. doi:10.1053/j.gastro.2008.01.073

    CAS  PubMed  Google Scholar 

  96. Mari M, Colell A, Morales A, von Montfort C, Garcia-Ruiz C, Fernandez-Checa JC (2010) Redox control of liver function in health and disease. Antioxid Redox Signal 12(11):1295–1331. doi:10.1089/ars.2009.2634

    PubMed Central  CAS  PubMed  Google Scholar 

  97. Mari M, Fernandez-Checa JC (2007) Sphingolipid signalling and liver diseases. Liver Int 27(4):440–450. doi:10.1111/j.1478-3231.2007.01475.x

    CAS  PubMed  Google Scholar 

  98. Mari M, Morales A, Colell A, Garcia-Ruiz C, Fernandez-Checa JC (2009) Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal 11(11):2685–2700. doi:10.1089/ARS.2009.2695

    PubMed Central  CAS  PubMed  Google Scholar 

  99. Matsubara M, Maruoka S, Katayose S (2002) Decreased plasma adiponectin concentrations in women with dyslipidemia. J Clin Endocrinol Metab 87(6):2764–2769. doi:10.1210/jcem.87.6.8550

    CAS  PubMed  Google Scholar 

  100. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ (1999) Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 116(6):1413–1419

    CAS  PubMed  Google Scholar 

  101. McClain CJ, Barve S, Deaciuc I (2007) Good fat/bad fat. Hepatology 45(6):1343–1346. doi:10.1002/hep.21788

    CAS  PubMed  Google Scholar 

  102. Mehal WZ (2013) The Gordian Knot of dysbiosis, obesity and NAFLD. Nat Rev Gastroenterol Hepatol 10(11):637–644. doi:10.1038/nrgastro.2013.146

    PubMed  Google Scholar 

  103. Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, Masciana R, Forgione A, Gabrieli ML, Perotti G, Vecchio FM, Rapaccini G, Gasbarrini G, Day CP, Grieco A (2009) Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49(6):1877–1887. doi:10.1002/hep.22848

    CAS  PubMed  Google Scholar 

  104. Miles JM, Nelson RH (2007) Contribution of triglyceride-rich lipoproteins to plasma free fatty acids. Horm Metab Res 39(10):726–729. doi:10.1055/s-2007-990273

    CAS  PubMed  Google Scholar 

  105. Montero J, Mari M, Colell A, Morales A, Basanez G, Garcia-Ruiz C, Fernandez-Checa JC (2010) Cholesterol and peroxidized cardiolipin in mitochondrial membrane properties, permeabilization and cell death. Biochim Biophys Acta 1797(6–7):1217–1224. doi:10.1016/j.bbabio.2010.02.010

    PubMed Central  CAS  PubMed  Google Scholar 

  106. Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417(1):1–13. doi:10.1042/BJ20081386

    PubMed Central  CAS  PubMed  Google Scholar 

  107. Musso G, Anty R, Petta S (2013) Antioxidant therapy and drugs interfering with lipid metabolism: could they be effective in NAFLD patients? Curr Pharm Des 19(29):5297–5313

    CAS  PubMed  Google Scholar 

  108. Musso G, Gambino R, Cassader M (2010) Gut microbiota as a regulator of energy homeostasis and ectopic fat deposition: mechanisms and implications for metabolic disorders. Curr Opin Lipidol 21(1):76–83. doi:10.1097/MOL.0b013e3283347ebb

    CAS  PubMed  Google Scholar 

  109. Neuschwander-Tetri BA (2010) Nontriglyceride hepatic lipotoxicity: the new paradigm for the pathogenesis of NASH. Curr Gastroenterol Rep 12(1):49–56. doi:10.1007/s11894-009-0083-6

    PubMed  Google Scholar 

  110. Neve EP, Ingelman-Sundberg M (2000) Molecular basis for the transport of cytochrome P450 2E1 to the plasma membrane. J Biol Chem 275(22):17130–17135. doi:10.1074/jbc.M000957200

    CAS  PubMed  Google Scholar 

  111. Orellana M, Rodrigo R, Varela N, Araya J, Poniachik J, Csendes A, Smok G, Videla LA (2006) Relationship between in vivo chlorzoxazone hydroxylation, hepatic cytochrome P450 2E1 content and liver injury in obese non-alcoholic fatty liver disease patients. Hepatol Res 34(1):57–63. doi:10.1016/j.hepres.2005.10.001

    CAS  PubMed  Google Scholar 

  112. Ota T, Gayet C, Ginsberg HN (2008) Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents. J Clin Invest 118(1):316–332. doi:10.1172/JCI32752

    PubMed Central  CAS  PubMed  Google Scholar 

  113. Ott M, Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S (2002) Cytochrome c release from mitochondria proceeds by a two-step process. Proc Natl Acad Sci U S A 99(3):1259–1263. doi:10.1073/pnas.241655498

    PubMed Central  CAS  PubMed  Google Scholar 

  114. Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, Engel J, Brownlee M, Scherer PE (2003) Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications for metabolic regulation and bioactivity. J Biol Chem 278(11):9073–9085. doi:10.1074/jbc.M207198200

    CAS  PubMed  Google Scholar 

  115. Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, Osterreicher CH, Takahashi H, Karin M (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140(2):197–208. doi:10.1016/j.cell.2009.12.052

    PubMed Central  CAS  PubMed  Google Scholar 

  116. 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. doi:10.1079/BJNBJN/2002544

    CAS  PubMed  Google Scholar 

  117. 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(4):999–1007. doi:10.1053/jhep.2003.50398

    CAS  PubMed  Google Scholar 

  118. Pessayre D (2007) Role of mitochondria in non-alcoholic fatty liver disease. J Gastroenterol Hepatol 22(Suppl 1):S20–S27. doi:10.1111/j.1440-1746.2006.04640.x

    CAS  PubMed  Google Scholar 

  119. Pessayre D, Fromenty B (2005) NASH: a mitochondrial disease. J Hepatol 42(6):928–940. doi:10.1016/j.jhep.2005.03.004

    CAS  PubMed  Google Scholar 

  120. Petersen DR, Doorn JA (2004) Reactions of 4-hydroxynonenal with proteins and cellular targets. Free Radic Biol Med 37(7):937–945. doi:10.1016/j.freeradbiomed.2004.06.012

    CAS  PubMed  Google Scholar 

  121. Postic C, Girard J (2008) Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest 118(3):829–838. doi:10.1172/JCI34275

    PubMed Central  CAS  PubMed  Google Scholar 

  122. Puri P, Baillie RA, Wiest MM, Mirshahi F, Choudhury J, Cheung O, Sargeant C, Contos MJ, Sanyal AJ (2007) A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 46(4):1081–1090. doi:10.1002/hep.21763

    CAS  PubMed  Google Scholar 

  123. Ramesh S, Sanyal AJ (2005) Evaluation and management of non-alcoholic steatohepatitis. J Hepatol 42(Suppl (1)):S2–S12. doi:10.1016/j.jhep.2004.11.022

    PubMed  Google Scholar 

  124. Rao MS, Reddy JK (2004) PPAR alpha in the pathogenesis of fatty liver disease. Hepatology 40(4):783–786. doi:10.1002/hep.20453

    CAS  PubMed  Google Scholar 

  125. Ray K (2013) NAFLD-the next global epidemic. Nat Rev Gastroenterol Hepatol 10(11):621. doi:10.1038/nrgastro.2013.197

    PubMed  Google Scholar 

  126. Reddy JK, Hashimoto T (2001) Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. Annu Rev Nutr 21:193–230. doi:10.1146/annurev.nutr.21.1.193

    CAS  PubMed  Google Scholar 

  127. Reddy JK, Rao MS (2006) Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol 290(5):G852–G858. doi:10.1152/ajpgi.00521.2005

    CAS  PubMed  Google Scholar 

  128. Ricci C, Pastukh V, Leonard J, Turrens J, Wilson G, Schaffer D, Schaffer SW (2008) Mitochondrial DNA damage triggers mitochondrial-superoxide generation and apoptosis. Am J Physiol Cell Physiol 294(2):C413–C422. doi:10.1152/ajpcell.00362.2007

    CAS  PubMed  Google Scholar 

  129. Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Allman M, Wallace M (2007) Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol 47(4):571–579. doi:10.1016/j.jhep.2007.04.019

    PubMed Central  CAS  PubMed  Google Scholar 

  130. Roh YS, Seki E (2013) Toll-like receptors in alcoholic liver disease, non-alcoholic steatohepatitis and carcinogenesis. J Gastroenterol Hepatol 28(Suppl 1):38–42. doi:10.1111/jgh.12019

    PubMed Central  CAS  PubMed  Google Scholar 

  131. Rolo AP, Teodoro JS, Palmeira CM (2012) Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic Biol Med 52(1):59–69. doi:10.1016/j.freeradbiomed.2011.10.003

    CAS  PubMed  Google Scholar 

  132. Samuel VT, Shulman GI (2012) Mechanisms for insulin resistance: common threads and missing links. Cell 148(5):852–871. doi:10.1016/j.cell.2012.02.017

    PubMed Central  CAS  PubMed  Google Scholar 

  133. 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(5):1183–1192. doi:10.1053/gast.2001.23256

    CAS  PubMed  Google Scholar 

  134. Schrader M, Fahimi HD (2006) Peroxisomes and oxidative stress. Biochim Biophys Acta 1763(12):1755–1766. doi:10.1016/j.bbamcr.2006.09.006

    CAS  PubMed  Google Scholar 

  135. Schwabe RF, Brenner DA (2006) Mechanisms of Liver Injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways. Am J Physiol Gastrointest Liver Physiol 290(4):G583–G589. doi:10.1152/ajpgi.00422.2005

    CAS  PubMed  Google Scholar 

  136. Schwenger KJ, Allard JP (2014) Clinical approaches to non-alcoholic fatty liver disease. World J Gastroenterol 20(7):1712–1723. doi:10.3748/wjg.v20.i7.1712

    PubMed Central  CAS  PubMed  Google Scholar 

  137. Serviddio G, Bellanti F, Tamborra R, Rollo T, Capitanio N, Romano AD, Sastre J, Vendemiale G, Altomare E (2008) Uncoupling protein-2 (UCP2) induces mitochondrial proton leak and increases susceptibility of non-alcoholic steatohepatitis (NASH) liver to ischaemia-reperfusion injury. Gut 57(7):957–965. doi:10.1136/gut.2007.147496

    CAS  PubMed  Google Scholar 

  138. Serviddio G, Bellanti F, Tamborra R, Rollo T, Romano AD, Giudetti AM, Capitanio N, Petrella A, Vendemiale G, Altomare E (2008) Alterations of hepatic ATP homeostasis and respiratory chain during development of non-alcoholic steatohepatitis in a rodent model. Eur J Clin Invest 38(4):245–252. doi:10.1111/j.1365-2362.2008.01936.x

    CAS  PubMed  Google Scholar 

  139. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116(11):3015–3025. doi:10.1172/JCI28898

    PubMed Central  CAS  PubMed  Google Scholar 

  140. Shimomura I, Bashmakov Y, Horton JD (1999) Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J Biol Chem 274(42):30028–30032

    CAS  PubMed  Google Scholar 

  141. Shklyaev S, Aslanidi G, Tennant M, Prima V, Kohlbrenner E, Kroutov V, Campbell-Thompson M, Crawford J, Shek EW, Scarpace PJ, Zolotukhin S (2003) Sustained peripheral expression of transgene adiponectin offsets the development of diet-induced obesity in rats. Proc Natl Acad Sci U S A 100(24):14217–14222. doi:10.1073/pnas.2333912100

    PubMed Central  CAS  PubMed  Google Scholar 

  142. Sies H (ed) (1985) Oxidative stress: introductory remarks. In: Oxidative stress. Academic, London

    Google Scholar 

  143. Son G, Kremer M, Hines IN (2010) Contribution of gut bacteria to liver pathobiology. Gastroenterol Res Pract 2010:453563. doi:10.1155/2010/453563

    PubMed Central  PubMed  Google Scholar 

  144. St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD (2002) Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 277(47):44784–44790. doi:10.1074/jbc.M207217200

    CAS  PubMed  Google Scholar 

  145. Su GL (2002) Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation. Am J Physiol Gastrointest Liver Physiol 283(2):G256–G265. doi:10.1152/ajpgi.00550.2001

    CAS  PubMed  Google Scholar 

  146. Summers SA (2006) Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res 45(1):42–72. doi:10.1016/j.plipres.2005.11.002

    CAS  PubMed  Google Scholar 

  147. Szabo G, Bala S, Petrasek J, Gattu A (2010) Gut-liver axis and sensing microbes. Dig Dis 28(6):737–744. doi:10.1159/000324281

    PubMed  Google Scholar 

  148. Teoh N, Field J, Farrell G (2006) Interleukin-6 is a key mediator of the hepatoprotective and pro-proliferative effects of ischaemic preconditioning in mice. J Hepatol 45(1):20–27. doi:10.1016/j.jhep.2006.01.039

    CAS  PubMed  Google Scholar 

  149. Tilg H (2010) The role of cytokines in non-alcoholic fatty liver disease. Dig Dis 28(1):179–185. doi:10.1159/000282083

    PubMed  Google Scholar 

  150. Tilg H, Moschen AR (2010) Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52(5):1836–1846. doi:10.1002/hep.24001

    CAS  PubMed  Google Scholar 

  151. Towle HC, Kaytor EN, Shih HM (1997) Regulation of the expression of lipogenic enzyme genes by carbohydrate. Annu Rev Nutr 17:405–433. doi:10.1146/annurev.nutr.17.1.405

    CAS  PubMed  Google Scholar 

  152. Triglyceride Coronary Disease Genetics C, Emerging Risk Factors C, Sarwar N, Sandhu MS, Ricketts SL, Butterworth AS, Di Angelantonio E, Boekholdt SM, Ouwehand W, Watkins H, Samani NJ, Saleheen D, Lawlor D, Reilly MP, Hingorani AD, Talmud PJ, Danesh J (2010) Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet 375(9726):1634–1639. doi:10.1016/S0140-6736(10)60545-4

    Google Scholar 

  153. Utzschneider KM, Kahn SE (2006) Review: the role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 91(12):4753–4761. doi:10.1210/jc.2006-0587

    CAS  PubMed  Google Scholar 

  154. van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI, Kench JG, London R, Peduto T, Chisholm DJ, George J (2008) Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology 48(2):449–457. doi:10.1002/hep.22350

    PubMed  Google Scholar 

  155. Vonghia L, Michielsen P, Francque S (2013) Immunological mechanisms in the pathophysiology of non-alcoholic steatohepatitis. Int J Mol Sci 14(10):19867–19890. doi:10.3390/ijms141019867

    PubMed Central  PubMed  Google Scholar 

  156. Wallace DC, Fan W (2010) Energetics, epigenetics, mitochondrial genetics. Mitochondrion 10(1):12–31. doi:10.1016/j.mito.2009.09.006

    PubMed Central  CAS  PubMed  Google Scholar 

  157. Watanabe A, Hashmi A, Gomes DA, Town T, Badou A, Flavell RA, Mehal WZ (2007) Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9. Hepatology 46(5):1509–1518. doi:10.1002/hep.21867

    CAS  PubMed  Google Scholar 

  158. Wei Y, Wang D, Gentile CL, Pagliassotti MJ (2009) Reduced endoplasmic reticulum luminal calcium links saturated fatty acid-mediated endoplasmic reticulum stress and cell death in liver cells. Mol Cell Biochem 331(1–2):31–40. doi:10.1007/s11010-009-0142-1

    PubMed Central  CAS  PubMed  Google Scholar 

  159. Wei Y, Wang D, Topczewski F, Pagliassotti MJ (2006) Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol Metab 291(2):E275–E281. doi:10.1152/ajpendo.00644.2005

    CAS  PubMed  Google Scholar 

  160. Welsh JA, Karpen S, Vos MB (2013) Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988-1994 to 2007-2010. J Pediatr 162(3):496–500. doi:10.1016/j.jpeds.2012.08.043

    PubMed Central  PubMed  Google Scholar 

  161. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA (2001) Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86(5):1930–1935. doi:10.1210/jcem.86.5.7463

    CAS  PubMed  Google Scholar 

  162. 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(1):124–131. doi:10.1053/j.gastro.2010.09.038

    PubMed  Google Scholar 

  163. Woodcroft KJ, Hafner MS, Novak RF (2002) Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression. Hepatology 35(2):263–273. doi:10.1053/jhep.2002.30691

    CAS  PubMed  Google Scholar 

  164. Wouters K, van Bilsen M, van Gorp PJ, Bieghs V, Lutjohann D, Kerksiek A, Staels B, Hofker MH, Shiri-Sverdlov R (2010) Intrahepatic cholesterol influences progression, inhibition and reversal of non-alcoholic steatohepatitis in hyperlipidemic mice. FEBS Lett 584(5):1001–1005. doi:10.1016/j.febslet.2010.01.046

    CAS  PubMed  Google Scholar 

  165. Wouters K, van Gorp PJ, Bieghs V, Gijbels MJ, Duimel H, Lutjohann D, Kerksiek A, van Kruchten R, Maeda N, Staels B, van Bilsen M, Shiri-Sverdlov R, Hofker MH (2008) Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis. Hepatology 48(2):474–486. doi:10.1002/hep.22363

    PubMed  Google Scholar 

  166. Wree A, Broderick L, Canbay A, Hoffman HM, Feldstein AE (2013) From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol 10(11):627–636. doi:10.1038/nrgastro.2013.149

    CAS  PubMed  Google Scholar 

  167. Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, Bhanot S, Monia BP, Li YX, Diehl AM (2007) Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 45(6):1366–1374. doi:10.1002/hep.21655

    CAS  PubMed  Google Scholar 

  168. Yang S, Zhu H, Li Y, Lin H, Gabrielson K, Trush MA, Diehl AM (2000) Mitochondrial adaptations to obesity-related oxidant stress. Arch Biochem Biophys 378(2):259–268. doi:10.1006/abbi.2000.1829

    CAS  PubMed  Google Scholar 

  169. Ye D, Li FY, Lam KS, Li H, Jia W, Wang Y, Man K, Lo CM, Li X, Xu A (2012) Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice. Gut 61(7):1058–1067. doi:10.1136/gutjnl-2011-300269

    CAS  PubMed  Google Scholar 

  170. Yki-Jarvinen H (2010) Liver fat in the pathogenesis of insulin resistance and type 2 diabetes. Dig Dis 28(1):203–209. doi:10.1159/000282087

    PubMed  Google Scholar 

  171. You M, Considine RV, Leone TC, Kelly DP, Crabb DW (2005) Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology 42(3):568–577. doi:10.1002/hep.20821

    PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona - Spanish National Research Council, IDIBAPS, Liver Unit-Hospital Clinic, Networked Biomedical Research Center for Hepatic and Digestive Disease, Barcelona, 08036, Spain

    Montserrat Marí

  2. Centre Esther Koplowitz, C/Rosselló 149-153, Barcelona, 08036, Spain

    Montserrat Marí

  3. Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona - Spanish National Research Council and Liver Unit-Hospital Clinic, Networked Biomedical Research Center for Hepatic and Digestive Diseases, Barcelona, 08036, Spain

    Albert Morales

  4. Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona - Spanish National Research Council, The August Pi i Sunyer Biomedical Research Institute, Liver Unit-Hospital Clínic, Networked Biomedical Research Center for Hepatic and Digestive Diseases, Barcelona, Spain

    Anna Colell

  5. Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Consejo Superior Investigaciones Científicas (CSIC) and Liver Unit-Hospital Clinic and Networked Biomedical Research Center for Hepatic and Digestive Diseases, Barcelona, 08036, Spain

    Carmen García-Ruiz

  6. Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    Carmen García-Ruiz

  7. Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council and Liver Unit-Hospital Clinic and CIBEREHD, Barcelona, Spain

    José C. Fernandez-Checa

  8. Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    José C. Fernandez-Checa

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  1. Montserrat Marí
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  2. Albert Morales
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  3. Anna Colell
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  4. Carmen García-Ruiz
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  5. José C. Fernandez-Checa
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Correspondence to Montserrat Marí .

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  1. Department of Health Sciences, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy

    Emanuele Albano

  2. Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, School of Medicine, University of Torino, Torino, Italy

    Maurizio Parola

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Marí, M., Morales, A., Colell, A., García-Ruiz, C., Fernandez-Checa, J.C. (2015). Oxidative Stress in Nonalcoholic Fatty Liver Disease. In: Albano, E., Parola, M. (eds) Studies on Hepatic Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Cham. https://doi.org/10.1007/978-3-319-15539-5_12

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