Oxidative Stress in Nonalcoholic Fatty Liver Disease

  • Montserrat MaríEmail author
  • Albert Morales
  • Anna Colell
  • Carmen García-Ruiz
  • José C. Fernandez-Checa
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)


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.


Nonalcoholic fatty liver disease Oxidative stress Free fatty acids Lipotoxicity Lipogenesis Steatosis Mitochondrial Dysfunction Cholesterol Glutathione Ceramide Reactive oxygen species CYP2E1 


  1. 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, ixPubMedGoogle Scholar
  2. 2.
    Adams LA, Lindor KD (2007) Nonalcoholic fatty liver disease. Ann Epidemiol 17(11):863–869. doi: 10.1016/j.annepidem.2007.05.013 PubMedGoogle Scholar
  3. 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):113–121PubMedGoogle Scholar
  4. 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 PubMedCentralPubMedGoogle Scholar
  5. 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 PubMedCentralPubMedGoogle Scholar
  6. 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 PubMedGoogle Scholar
  7. 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 PubMedGoogle Scholar
  8. 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):5678–5684PubMedGoogle Scholar
  9. 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 PubMedGoogle Scholar
  10. 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 PubMedGoogle Scholar
  11. 11.
    Bidlack WR, Brown RC, Mohan C (1986) Nutritional parameters that alter hepatic drug metabolism, conjugation, and toxicity. Fed Proc 45(2):142–148PubMedGoogle Scholar
  12. 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 PubMedGoogle Scholar
  13. 13.
    Bogenhagen DF (1999) Repair of mtDNA in vertebrates. Am J Hum Genet 64(5):1276–1281. doi: 10.1086/302392 PubMedCentralPubMedGoogle Scholar
  14. 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 PubMedGoogle Scholar
  15. 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 PubMedGoogle Scholar
  16. 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 PubMedGoogle Scholar
  17. 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):430–434PubMedGoogle Scholar
  18. 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):1659–1664PubMedGoogle Scholar
  19. 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):1379–1383PubMedGoogle Scholar
  20. 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 PubMedCentralPubMedGoogle Scholar
  21. 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 PubMedGoogle Scholar
  22. 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):5692–5700PubMedGoogle Scholar
  23. 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 PubMedCentralPubMedGoogle Scholar
  24. 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 PubMedGoogle Scholar
  25. 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 PubMedCentralPubMedGoogle Scholar
  26. 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 PubMedGoogle Scholar
  27. 27.
    Day CP (2002) Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol 16(5):663–678PubMedGoogle Scholar
  28. 28.
    Day CP (2006) From fat to inflammation. Gastroenterology 130(1):207–210. doi: 10.1053/j.gastro.2005.11.017 PubMedGoogle Scholar
  29. 29.
    Day CP, James OF (1998) Steatohepatitis: a tale of two “hits”? Gastroenterology 114(4):842–845PubMedGoogle Scholar
  30. 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):219–223PubMedGoogle Scholar
  31. 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 PubMedGoogle Scholar
  32. 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 PubMedGoogle Scholar
  33. 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 PubMedCentralPubMedGoogle Scholar
  34. 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 PubMedCentralPubMedGoogle Scholar
  35. 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 PubMedGoogle Scholar
  36. 36.
    Eaton S, Bartlett K, Pourfarzam M (1996) Mammalian mitochondrial beta-oxidation. Biochem J 320(Pt 2):345–357PubMedCentralPubMedGoogle Scholar
  37. 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 PubMedGoogle Scholar
  38. 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):205–211PubMedGoogle Scholar
  39. 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):614–621Google Scholar
  40. 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 PubMedGoogle Scholar
  41. 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 PubMedCentralPubMedGoogle Scholar
  42. 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 386:111–135PubMedGoogle Scholar
  43. 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 PubMedCentralPubMedGoogle Scholar
  44. 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):437–443PubMedGoogle Scholar
  45. 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 PubMedCentralPubMedGoogle Scholar
  46. 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 PubMedGoogle Scholar
  47. 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 PubMedCentralPubMedGoogle Scholar
  48. 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. 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 PubMedCentralPubMedGoogle Scholar
  50. 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 PubMedGoogle Scholar
  51. 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 PubMedCentralPubMedGoogle Scholar
  52. 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):11369–11377PubMedGoogle Scholar
  53. 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 PubMedGoogle Scholar
  54. 54.
    Goldfischer SL (1988) Peroxisomal diseases. Prog Clin Biol Res 282:117–137PubMedGoogle Scholar
  55. 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 PubMedGoogle Scholar
  56. 56.
    Guicciardi ME, Leist M, Gores GJ (2004) Lysosomes in cell death. Oncogene 23(16):2881–2890. doi: 10.1038/sj.onc.1207512 PubMedGoogle Scholar
  57. 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):3346–3354PubMedGoogle Scholar
  58. 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. 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 PubMedGoogle Scholar
  60. 60.
    Hermesh O, Kalderon B, Bar-Tana J (1998) Mitochondria uncoupling by a long chain fatty acyl analogue. J Biol Chem 273(7):3937–3942PubMedGoogle Scholar
  61. 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):16484–16493PubMedGoogle Scholar
  62. 62.
    Hotamisligil GS, Spiegelman BM (1994) Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes 43(11):1271–1278PubMedGoogle Scholar
  63. 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):1595–1599PubMedGoogle Scholar
  64. 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):595–604PubMedGoogle Scholar
  65. 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 PubMedGoogle Scholar
  66. 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 PubMedGoogle Scholar
  67. 67.
    Hussain MM, Shi J, Dreizen P (2003) Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res 44(1):22–32PubMedGoogle Scholar
  68. 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 PubMedGoogle Scholar
  69. 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 PubMedCentralPubMedGoogle Scholar
  70. 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 PubMedGoogle Scholar
  71. 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 PubMedGoogle Scholar
  72. 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 PubMedCentralPubMedGoogle Scholar
  73. 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 PubMedGoogle Scholar
  74. 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 PubMedCentralPubMedGoogle Scholar
  75. 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 PubMedCentralPubMedGoogle Scholar
  76. 76.
    Kim CH, Younossi ZM (2008) Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome. Cleve Clin J Med 75(10):721–728PubMedGoogle Scholar
  77. 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 PubMedGoogle Scholar
  78. 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):351–358PubMedGoogle Scholar
  79. 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 PubMedGoogle Scholar
  80. 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 PubMedCentralPubMedGoogle Scholar
  81. 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 PubMedGoogle Scholar
  82. 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 PubMedGoogle Scholar
  83. 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 PubMedGoogle Scholar
  84. 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 PubMedCentralPubMedGoogle Scholar
  85. 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 PubMedCentralPubMedGoogle Scholar
  86. 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 PubMedCentralPubMedGoogle Scholar
  87. 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. 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 PubMedCentralPubMedGoogle Scholar
  89. 89.
    Loomba R, Sanyal AJ (2013) The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 10(11):686–690. doi: 10.1038/nrgastro.2013.171 PubMedGoogle Scholar
  90. 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 PubMedCentralPubMedGoogle Scholar
  91. 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 PubMedGoogle Scholar
  92. 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 PubMedCentralPubMedGoogle Scholar
  93. 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 PubMedGoogle Scholar
  94. 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 PubMedGoogle Scholar
  95. 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 PubMedGoogle Scholar
  96. 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 PubMedCentralPubMedGoogle Scholar
  97. 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 PubMedGoogle Scholar
  98. 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 PubMedCentralPubMedGoogle Scholar
  99. 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 PubMedGoogle Scholar
  100. 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):1413–1419PubMedGoogle Scholar
  101. 101.
    McClain CJ, Barve S, Deaciuc I (2007) Good fat/bad fat. Hepatology 45(6):1343–1346. doi: 10.1002/hep.21788 PubMedGoogle Scholar
  102. 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 PubMedGoogle Scholar
  103. 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 PubMedGoogle Scholar
  104. 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 PubMedGoogle Scholar
  105. 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 PubMedCentralPubMedGoogle Scholar
  106. 106.
    Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417(1):1–13. doi: 10.1042/BJ20081386 PubMedCentralPubMedGoogle Scholar
  107. 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):5297–5313PubMedGoogle Scholar
  108. 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 PubMedGoogle Scholar
  109. 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 PubMedGoogle Scholar
  110. 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 PubMedGoogle Scholar
  111. 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 PubMedGoogle Scholar
  112. 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 PubMedCentralPubMedGoogle Scholar
  113. 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 PubMedCentralPubMedGoogle Scholar
  114. 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 PubMedGoogle Scholar
  115. 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 PubMedCentralPubMedGoogle Scholar
  116. 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 PubMedGoogle Scholar
  117. 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 PubMedGoogle Scholar
  118. 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 PubMedGoogle Scholar
  119. 119.
    Pessayre D, Fromenty B (2005) NASH: a mitochondrial disease. J Hepatol 42(6):928–940. doi: 10.1016/j.jhep.2005.03.004 PubMedGoogle Scholar
  120. 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 PubMedGoogle Scholar
  121. 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 PubMedCentralPubMedGoogle Scholar
  122. 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 PubMedGoogle Scholar
  123. 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 PubMedGoogle Scholar
  124. 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 PubMedGoogle Scholar
  125. 125.
    Ray K (2013) NAFLD-the next global epidemic. Nat Rev Gastroenterol Hepatol 10(11):621. doi: 10.1038/nrgastro.2013.197 PubMedGoogle Scholar
  126. 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 PubMedGoogle Scholar
  127. 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 PubMedGoogle Scholar
  128. 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 PubMedGoogle Scholar
  129. 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 PubMedCentralPubMedGoogle Scholar
  130. 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 PubMedCentralPubMedGoogle Scholar
  131. 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 PubMedGoogle Scholar
  132. 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 PubMedCentralPubMedGoogle Scholar
  133. 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 PubMedGoogle Scholar
  134. 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 PubMedGoogle Scholar
  135. 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 PubMedGoogle Scholar
  136. 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 PubMedCentralPubMedGoogle Scholar
  137. 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 PubMedGoogle Scholar
  138. 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 PubMedGoogle Scholar
  139. 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 PubMedCentralPubMedGoogle Scholar
  140. 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):30028–30032PubMedGoogle Scholar
  141. 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 PubMedCentralPubMedGoogle Scholar
  142. 142.
    Sies H (ed) (1985) Oxidative stress: introductory remarks. In: Oxidative stress. Academic, LondonGoogle Scholar
  143. 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 PubMedCentralPubMedGoogle Scholar
  144. 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 PubMedGoogle Scholar
  145. 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 PubMedGoogle Scholar
  146. 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 PubMedGoogle Scholar
  147. 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 PubMedGoogle Scholar
  148. 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 PubMedGoogle Scholar
  149. 149.
    Tilg H (2010) The role of cytokines in non-alcoholic fatty liver disease. Dig Dis 28(1):179–185. doi: 10.1159/000282083 PubMedGoogle Scholar
  150. 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 PubMedGoogle Scholar
  151. 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 PubMedGoogle Scholar
  152. 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. 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 PubMedGoogle Scholar
  154. 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 PubMedGoogle Scholar
  155. 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 PubMedCentralPubMedGoogle Scholar
  156. 156.
    Wallace DC, Fan W (2010) Energetics, epigenetics, mitochondrial genetics. Mitochondrion 10(1):12–31. doi: 10.1016/j.mito.2009.09.006 PubMedCentralPubMedGoogle Scholar
  157. 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 PubMedGoogle Scholar
  158. 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 PubMedCentralPubMedGoogle Scholar
  159. 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 PubMedGoogle Scholar
  160. 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 PubMedCentralPubMedGoogle Scholar
  161. 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 PubMedGoogle Scholar
  162. 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 PubMedGoogle Scholar
  163. 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.2002.30691PubMedGoogle Scholar
  164. 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 PubMedGoogle Scholar
  165. 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 PubMedGoogle Scholar
  166. 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 PubMedGoogle Scholar
  167. 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 PubMedGoogle Scholar
  168. 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 PubMedGoogle Scholar
  169. 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 PubMedGoogle Scholar
  170. 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 PubMedGoogle Scholar
  171. 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 PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Montserrat Marí
    • 1
    • 2
    Email author
  • Albert Morales
    • 3
  • Anna Colell
    • 4
  • Carmen García-Ruiz
    • 5
    • 6
  • José C. Fernandez-Checa
    • 7
    • 8
  1. 1.Department of Cell Death and ProliferationInstitute of Biomedical Research of Barcelona - Spanish National Research Council, IDIBAPS, Liver Unit-Hospital Clinic, Networked Biomedical Research Center for Hepatic and Digestive DiseaseBarcelonaSpain
  2. 2.Centre Esther KoplowitzBarcelonaSpain
  3. 3.Department of Cell Death and ProliferationInstitute of Biomedical Research of Barcelona - Spanish National Research Council and Liver Unit-Hospital Clinic, Networked Biomedical Research Center for Hepatic and Digestive DiseasesBarcelonaSpain
  4. 4.Department of Cell Death and ProliferationInstitute 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 DiseasesBarcelonaSpain
  5. 5.Department of Cell Death and ProliferationInstitute 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 DiseasesBarcelonaSpain
  6. 6.Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern CaliforniaLos AngelesUSA
  7. 7.Department of Cell Death and ProliferationInstitute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council and Liver Unit-Hospital Clinic and CIBEREHDBarcelonaSpain
  8. 8.Southern California Research Center for ALPD and CirrhosisKeck School of Medicine of the University of Southern CaliforniaLos AngelesUSA

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