Redox homeostasis and epigenetics in non-alcoholic fatty liver disease (NAFLD)

Current Pharmaceutical Design

Volumn 19, Issue 15, 2013, Pages 2737-2746

  Podrini, Christine ^a   Borghesan, Michela ^a   Greco, Azzura ^a   Pazienza, Valerio ^b   Mazzoccoli, Gianluigi ^b   Vinciguerra, Manlio ^c,d  

^a INSTITUTE OF HEPATOLOGY   (United Kingdom)

^b CASA SOLLIEVO DELLA SOFFERENZA HOSPITAL   (Italy)

^c Euro Mediterranean Institute of Science and Technology   (Italy)

^d UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

Epigenetics; Non alcoholic fatty liver disease (NAFLD); Oxidative stress

Indexed keywords

ARTICLE; CARDIOVASCULAR DISEASE; EPIGENETICS; GENE EXPRESSION; GENE SILENCING; GLUCONEOGENESIS; HOMEOSTASIS; HUMAN; LIPID METABOLISM; LIVER CELL; NONALCOHOLIC FATTY LIVER DISEASE ACTIVITY SCORE; NONHUMAN; OXIDATION REDUCTION REACTION; OXIDATIVE STRESS; PATHOGENESIS; PRIORITY JOURNAL;

CARDIOVASCULAR DISEASES; EPIGENESIS, GENETIC; FATTY LIVER; HOMEOSTASIS; HUMANS; OXIDATION-REDUCTION; OXIDATIVE STRESS;

EID: 84876727580     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/1381612811319150009     Document Type: Article

References (166)

1. Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology.; 51(2): 679-689.
2. Malhi H, Guicciardi ME, Gores GJ. Hepatocyte death: a clear and present danger. Physiol Rev 2010; 90(3): 1165-1194.
3. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 2003; 37(5): 1202-1219.
4. Petta S, Muratore C, Craxi A. Non-alcoholic fatty liver disease pathogenesis: the present and the future. Dig Liver Dis 2009; 41(9): 615-625.
5. Myers RP. Noninvasive diagnosis of nonalcoholic fatty liver disease. Ann Hepatol 2009; 8 Suppl 1: S25-S33.
6. Sass DA, Chang P, Chopra KB. Nonalcoholic fatty liver disease: a clinical review. Dig Dis Sci 2005; 50(1): 171-180.
7. Kantartzis K, Schick F, Haring HU, Stefan N. Environmental and genetic determinants of fatty liver in humans. Dig Dis 2010; 28(1): 169-178.
8. Day CP, James OF. Steatohepatitis: a tale of two hits? Gastroenterology 1998; 114(4): 842-845.
9. Anstee QM, Goldin RD. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol 2006; 87(1): 1-16.
10. Bieghs V, Van Gorp PJ, Wouters K, Hendrikx T, Gijbels MJ, van Bilsen M, et al. LDL receptor knock-out mice are a physiological model particularly vulnerable to study the onset of inflammation in non-alcoholic fatty liver disease. PLoS ONE 2012; 7(1): e30668.
11. Bieghs V, van Gorp PJ, Walenbergh S, Gijbels MJ, Verheyen F, Buurman WA, et al. Specific immunization strategies a gainst oxidized LDL: A novel way to reduce non-alcoholic steatohepa titis in mice. Hepatology 2012 Feb 15.
12. Pogribny IP, Tryndyak VP, Bagnyukova TV, Melnyk S, Montgomery B, Ross SA, et al. Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet. J Hepatol 2009; 51(1): 176-86.
13. Feinberg AP. Phenotypic plasticity and the epigenetics of human disease. Nature 2007 May 24; 447(7143): 433-40.
14. Feinberg AP. Epigenetics at the epicenter of modern medicine. JAMA 2008 Mar 19; 299(11): 1345-50.
15. Youngson NA, Whitelaw E. Transgenerational epigenetic effects. Annu Rev Genomics Hum Genet 2008; 9: 233-57.
16. Daxinger L, Whitelaw E. Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat Rev Genet 2012; 13(3): 153-62.
17. Robertson G, Leclercq I, Farrell GC. Nonalcoholic steatosis and steatohepatitis. II. Cytochrome P-450 enzymes and oxidative stress. Am J Physiol Gastrointest Liver Physiol 2001; 281(5): G1135-9.
18. Bergamini CM, Gambetti S, Dondi A, Cervellati C. Oxygen, reactive oxygen species and tissue damage. Curr Pharm Des 2004; 10(14): 1611-26.
19. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 2004; 114(2): 147-52.
20. Seki S, Kitada T, Yamada T, Sakaguchi H, Nakatani K, Wakasa K. In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases. J Hepatol 2002; 37(1): 56-62.
21. Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res 2009; 48(1): 1-26.
22. Utzschneider KM, Kahn SE. Review: The role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2006; 91(12): 4753-61.
23. Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest 2008; 118(3): 829-38.
24. Lewis GF, Carpentier A, Adeli K, Giacca A. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 2002; 23(2): 201-29.
25. De Gottardi A, Vinciguerra M, Sgroi A, Moukil M, Ravier-Dall'Antonia F, Pazienza V, et al. Microarray analyses and molecular profiling of steatosis induction in immortalized human hepatocytes. Lab Invest 2007; 87(8): 792-806.
26. Lou-Bonafonte JM, Arnal C, Osada J. New genes involved in hepatic steatosis. Curr Opin Lipidol 2011; 22(3): 159-64.
27. Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, et al. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 2004; 113(12): 1774-83.
28. Vinciguerra M, Carrozzino F, Peyrou M, Carlone S, Montesano R, Benelli R, et al. Unsaturated fatty acids promote hepatoma proliferation and progression through downregulation of the tumor suppressor PTEN. J Hepatol 2009; 50(6): 1132-41.
29. Vinciguerra M, Foti M. PTEN and SHIP2 phosphoinositide phosphatases as negative regulators of insulin signalling. Arch Physiol Biochem 2006; 112(2): 89-104.
30. Vinciguerra M, Foti M. PTEN at the crossroad of metabolic diseases and cancer in the liver. Ann Hepatol 2008 Jul-Sep; 7(3): 192-9.
31. Vinciguerra M, Sgroi A, Veyrat-Durebex C, Rubbia-Brandt L, Buhler LH, Foti M. Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes. Hepatology 2009; 49(4): 1176-84.
32. Vinciguerra M, Veyrat-Durebex C, Moukil MA, Rubbia-Brandt L, Rohner-Jeanrenaud F, Foti M. PTEN down-regulation by unsaturated fatty acids triggers hepatic steatosis via an NFkappaBp65/ mTOR-dependent mechanism. Gastroenterology 2008; 134(1): 268-80.
33. Clement S, Peyrou M, Sanchez-Pareja A, Bourgoin L, Ramadori P, Suter D, et al. Down-regulation of phosphatase and tensin homolog by hepatitis C virus core 3a in hepatocytes triggers the formation of large lipid droplets. Hepatology 2011; 54(1): 38-49.
34. Leavens KF, Easton RM, Shulman GI, Previs SF, Birnbaum MJ. Akt2 is required for hepatic lipid accumulation in models of insulin resistance. Cell Metab 2009; 10(5): 405-18.
35. He L, Hou X, Kanel G, Zeng N, Galicia V, Wang Y, et al. The critical role of AKT2 in hepatic steatosis induced by PTEN loss. Am J Pathol 2010; 176(5): 2302-8.
36. Horton JD. Sterol regulatory element-binding proteins: transcriptional activators of lipid synthesis. Biochem Soc Trans 2002; 30(Pt 6): 1091-5.
37. Haeusler RA, Han S, Accili D. Hepatic FoxO1 ablation exacerbates lipid abnormalities during hyperglycemia. J Biol Chem 2010 Aug 27; 285(35): 26861-8.
38. Kersten S. Mechanisms of nutritional and hormonal regulation of lipogenesis. EMBO Rep 2001; 2(4): 282-6.
39. Schwarz JM, Linfoot P, Dare D, Aghajanian K. Hepatic de novo lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat, highcarbohydrate isoenergetic diets. Am J Clin Nutr 2003; 77(1): 43-50.
40. Iizuka K, Bruick RK, Liang G, Horton JD, Uyeda K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc Natl Acad Sci U S A 2004 May 11; 101(19): 7281-6.
41. Pettinelli P, Del Pozo T, Araya J, Rodrigo R, Araya AV, Smok G, et al. Enhancement in liver SREBP-1c/PPAR-alpha ratio and steatosis in obese patients: correlations with insulin resistance and n-3 long-chain polyunsaturated fatty acid depletion. Biochim Biophys Acta 2009; 1792(11): 1080-6.
42. Ducheix S, Lobaccaro JM, Martin PG, Guillou H. Liver X Receptor: an oxysterol sensor and a major player in the control of lipogenesis. Chem Phys Lipids 2011; 164(6): 500-14.
43. Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, et al. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 1998 May 29; 93(5): 693-704.
44. Im SS, Osborne TF. Liver x receptors in atherosclerosis and inflammation. Circ Res 2011 Apr 15; 108(8): 996-1001.
45. Fievet C, Staels B. Combination therapy of statins and fibrates in the management of cardiovascular risk. Curr Opin Lipidol 2009; 20(6): 505-11.
46. Lee JH, Wada T, Febbraio M, He J, Matsubara T, Lee MJ, et al. A novel role for the dioxin receptor in fatty acid metabolism and hepatic steatosis. Gastroenterology 2010; 139(2): 653-63.
47. Kang HS, Okamoto K, Kim YS, Takeda Y, Bortner CD, Dang H, et al. Nuclear orphan receptor TAK1/TR4-deficient mice are protected against obesity-linked inflammation, hepatic steatosis, and insulin resistance. Diabetes 2011; 60(1): 177-88.
48. Zhang N, Fu Z, Linke S, Chicher J, Gorman JJ, Visk D, et al. The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism. Cell Metab 2010 May 5; 11(5): 364-78.
49. Cermelli S, Ruggieri A, Marrero JA, Ioannou GN, Beretta L. Circulating microRNAs in patients with chronic hepatitis C and nonalcoholic fatty liver disease. PLoS ONE 2011; 6(8): e23937.
50. Dowman JK, Tomlinson JW, Newsome PN. Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and nonalcoholic steatohepatitis. Aliment Pharmacol Ther 2010; 33(5): 525-40.
51. Fujii H, Kawada N. Inflammation and fibrogenesis in steatohepatitis. J Gastroenterol 2012; 47(3): 215-25.
52. Baffy G. Kupffer cells in non-alcoholic fatty liver disease: the emerging view. J Hepatol 2009; 51(1): 212-23.
53. Tschopp J, Schroder K. NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nat Rev Immunol 2010; 10(3): 210-5.
54. Henao-Mejia J, Elinav E, Jin C, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature.; 482(7384): 179-85.
55. Fowler JC, Zecchini VR, Jones PH. Intestinal activation of Notch signaling induces rapid onset hepatic steatosis and insulin resistance. PLoS ONE 2011; 6(6): e20767.
56. Corbin KD, Zeisel SH. Choline metabolism provides novel insights into nonalcoholic fatty liver disease and its progression. Curr Opin Gastroenterol 2012; 28(2): 159-65.
57. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol 2010; 28(10): 1057-68.
58. Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis 2010; 31(1): 27-36.
59. Sawan C, Vaissiere T, Murr R, Herceg Z. Epigenetic drivers and genetic passengers on the road to cancer. Mutat Res 2008; 642(1-2): 1-13.
60. Gertych A, Farkas DL, Tajbakhsh J. Measuring topology of lowintensity DNA methylation sites for high-throughput assessment of epigenetic drug-induced effects in cancer cells. Exp Cell Res 2010; 316(19): 3150-60.
61. Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000; 403(6765): 41-5.
62. Lennartsson A, Ekwall K. Histone modification patterns and epigenetic codes. Biochim Biophys Acta 2009; 1790(9): 863-8.
63. Gibbs JR, van der Brug MP, Hernandez DG, et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet 2011; 6(5): e1000952.
64. Dudley KJ, Sloboda DM, Connor KL, Beltrand J, Vickers MH. Offspring of mothers fed a high fat diet display hepatic cell cycle inhibition and associated changes in gene expression and DNA methylation. PLoS ONE 2011; 6(7): e21662.
65. Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 2010; 467(7318): 963-6.
66. Curley JP, Mashoodh R, Champagne FA. Epigenetics and the origins of paternal effects. Horm Behav 2011; 59(3): 306-14.
67. Feng D, Liu T, Sun Z, et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 2011 Mar 11; 331(6022): 1315-9.
68. Purushotham A, Schug, TT, Xu, Q, Surapureddi, S, Guo, X, Li, X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab 2009; 9(4): 327-38.
69. Guarente L. Franklin H. Epstein Lecture: Sirtuins, aging, and medicine. N Engl J Med 2011 Jun 9; 364(23): 2235-44.
70. Vinciguerra M, Santini MP, Martinez C, et al. mIGF-1/JNK1/SirT1 signaling confers protection against oxidative stress in the heart. Aging Cell 2012; 11(1): 139-49.
71. Vinciguerra M, Fulco M, Ladurner A, Sartorelli V, Rosenthal N. SirT1 in muscle physiology and disease: lessons from mouse models. Dis Model Mech 2010; 3(5-6): 298-303.
72. Vinciguerra M, Santini MP, Claycomb WC, Ladurner AG, Rosenthal N. Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activity. Aging (Albany NY) 2009; 2(1): 43-62.
73. Mazzoccoli G, Pazienza V, Vinciguerra M. Clock genes and clockcontrolled genes in the regulation of metabolic rhythms. Chronobiol Int 2012; 29(3): 227-51.
74. Tonkin J, Villarroya F, Puri PL, Vinciguerra M. SIRT1 signaling as potential modulator of skeletal muscle diseases. Curr Opin Pharmacol 2012 Mar 6.
75. Pazienza V, Piepoli A, Panza A, Valvano MR, Benegiamo G, Vinciguerra M, et al. SIRT1 and the clock gene machinery in colorectal cancer. Cancer Invest 2012; 30(2): 98-105.
76. Feige J, Auwerx, J. Transcriptional targets of sirtuins in the coordination of mammalian physiology. Curr Opin Cell Biol 2008; 20(3): 303-9.
77. Horio Y. Diabetes: Insulin signal meets SIRT1 at AKT. Nat Rev Endocrinol 2011; 8(3): 131-2.
78. Lee J, Padhye A, Sharma A, et al. A pathway involving farnesoid X receptor and small heterodimer partner positively regulates hepatic sirtuin 1 levels via microRNA-34a inhibition. J Biol Chem 2010; 285(17): 12604-11.
79. Li X, Zhang S, Blander G, Tse JG, Krieger M, Guarente L. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol Cell 2007; 28(1): 91-106.
80. Kemper JK, Xiao Z, Ponugoti B, et al. FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab 2009; 10(5): 392-404.
81. Li X, Kazgan N. Mammalian sirtuins and energy metabolism. Int J Biol Sci 2011; 7(5): 575-87.
82. Gao Z, Zhang J, Kheterpal I, Kennedy N, Davis RJ, Ye J. Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun Nterminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity. J Biol Chem 2011; 286(25): 22227-34.
83. Guarani V, Deflorian G, Franco CA, et al. Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase. Nature 2011; 473(7346): 234-8.
84. Sciacca S, Pilato M, Mazzoccoli G, Pazienza V, Vinciguerra M. Anti-correlation between longevity gene SirT1 and Notch signaling in ascending aorta biopsies from patients with bicuspid aortic valve disease. Heart Vessels 2012 Feb 28; [Epub ahead of print].
85. Pfluger P, Herranz D, Velasco-Miguel S, Serrano M, Tscĥp MH. Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A 2008; 105(28): 9793-8.
86. Singh UP, Singh NP, Singh B, et al. Resveratrol (trans-3,5,4'-trihydroxystilbene) induces silent mating type information regulation-1 and down-regulates nuclear transcription factor-kappaB activation to abrogate dextran sulfate sodium-induced colitis. J Pharmacol Exp Ther 2011; 332(3): 829-39.
87. Warnke I, Goralczyk R, Fuhrer E, Schwager J. Dietary constituents reduce lipid accumulation in murine C3H10 T1/2 adipocytes: A novel fluorescent method to quantify fat droplets. Nutr Metab (Lond) 2011; 8(1): 30.
88. Bishayee A, Dhir N. Resveratrol-mediated chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis: inhibition of cell proliferation and induction of apoptosis. Chem Biol Interact 2009; 179(2-3): 131-44.
89. Hou X, Xu S, Maitland-Toolan KA, et al. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem 2008; 283(29): 20015-26.
90. Um JH, Park SJ, Kang H, et al. AMP-activated protein kinasedeficient mice are resistant to the metabolic effects of resveratrol. Diabetes 2010; 59(3): 554-63.
91. Cederroth CR, Vinciguerra M, Gjinovci A, et al. Dietary phytoestrogens activate AMP-activated protein kinase with improvement in lipid and glucose metabolism. Diabetes 2008; 57(5): 1176-85.
92. Canto C, Gerhart-Hines Z, Feige JN, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 2009; 458(7241): 1056-60.
93. Park SJ, Ahmad F, Philp A, et al. Resveratrol ameliorates agingrelated metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 2012; 148(3): 421-33.
94. Gamble MJ, Kraus WL. Multiple facets of the unique histone variant macroH2A: From genomics to cell biology. Cell Cycle 2010; 9(13).
95. Gamble M, Frizzell KM, Yang C, Krishnakumar R, Kraus WL. The histone variant macroH2A1 marks repressed autosomal chromatin, but protects a subset of its target genes from silencing. Genes Dev 2010; 24(1): 21-32.
96. Boulard M, Storck S, Cong R, Pinto R, Delage H, Bouvet P. Histone variant macroH2A1 deletion in mice causes female-specific steatosis. Epigenetics Chromatin 2010; 3(1): 8. [Epub ahead of print].
97. Changolkar L, Costanzi C, Leu NA, Chen D, McLaughlin KJ, Pehrson JR. Developmental changes in histone macroH2A1-mediated gene regulation. Mol Cell Biol 2007; 27(7): 2758-64.
98. Kustatscher G, Hothorn M, Pugieux C, Scheffzek K, Ladurner AG. Splicing regulates NAD metabolite binding to histone macroH2A. Nat Struct Mol Biol 2005; 12(7): 624-5.
99. Sporn J, Kustatscher G, Hothorn T, et al. Histone macroH2A isoforms predict the risk of lung cancer recurrence. Oncogene 2009; Aug 3. [Epub ahead of print].
100. Kapoor A, Goldberg MS, Cumberland LK, et al. The histone variant macroH2A suppresses melanoma progression through regulation of CDK8. Nature 2010; 468(7327): 1105-9.
101. Changolkar LN, Singh G, Cui K, et al. Genome-Wide Distribution of MacroH2A1 Histone Variants in Mouse Liver Chromatin. Mol Cell Biol 2010 Oct 11.
102. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363(14): 1341-50.
103. Bonapace S, Perseghin G, Molon G, et al. Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes. Diabetes Care 2012; 35(2): 389-95.
104. Ouwens DM, Boer C, Fodor M, et al. Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats. Diabetologia 2005; 48(6): 1229-37.
105. Martinez de Morentin PB, Varela L, Ferno J, Nogueiras R, Dieguez C, Lopez M. Hypothalamic lipotoxicity and the metabolic syndrome. Biochim Biophys Acta 2010; 1801(3): 350-61.
106. Fotbolcu H, Yakar T, Duman D, et al. Impairment of the left ventricular systolic and diastolic function in patients with nonalcoholic fatty liver disease. Cardiol J 2010; 17(5): 457-63.
107. Hamaguchi M, Kojima T, Takeda N, et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol 2007; 13(10): 1579-84.
108. Targher G, Bertolini L, Rodella S, et al. NASH predicts plasma inflammatory biomarkers independently of visceral fat in men. Obesity (Silver Spring) 2008; 16(6): 1394-9.
109. Fontana L, Vinciguerra M, Longo VD. Growth factors, nutrient signaling, and cardiovascular aging. Circ Res 2012 Apr 13; 110(8): 1139-50.
110. Brea A, Mosquera D, Martin E, Arizti A, Cordero JL, Ros E. Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case-control study. Arterioscler Thromb Vasc Biol 2005; 25(5): 1045-50.
111. Cooper ME, El-Osta A. Epigenetics: mechanisms and implications for diabetic complications. Circ Res 2010; 107(12): 1403-13.
112. Ordovas JM, Smith CE. Epigenetics and cardiovascular disease. Nat Rev Cardiol 2010; 7(9): 510-9.
113. Baccarelli A, Tarantini L, Wright RO, et al. Repetitive element DNA methylation and circulating endothelial and inflammation markers in the VA normative aging study. Epigenetics 2010; 5(3).
114. Lund G, Andersson L, Lauria M, et al. DNA methylation polymorphisms precede any histological sign of atherosclerosis in mice lacking apolipoprotein E. J Biol Chem 2004; 279(28): 29147-54.
115. Erlinger S. Do patients with nonalcoholic fatty liver disease die from their heart? Clin Res Hepatol Gastroenterol 2011; 35(3): 163-5.
116. Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 2006; 160(1): 1-40.
117. Circu ML, Aw TY. Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med 2010; 48(6): 749-62.
118. Ha HL, Yu DY. HBx-induced reactive oxygen species activates hepatocellular carcinogenesis via dysregulation of PTEN/Akt pathway. World J Gastroenterol 2010; 16(39): 4932-7.
119. Savu O, Sunkari VG, Botusan IR, Grunler J, Nikoshkov A, Catrina SB. Stability of mitochondrial DNA against reactive oxygen species (ROS) generated in diabetes. Diabetes Metab Res Rev 2011; 27(5): 470-9.
120. Begriche K, Igoudjil A, Pessayre D, Fromenty B. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion 2006; 6(1): 1-28.
121. Le TH, Caldwell SH, Redick JA, et al. The zonal distribution of megamitochondria with crystalline inclusions in nonalcoholic steatohepatitis. Hepatology 2004; 39(5): 1423-9.
122. Zhang D, Liu ZX, Choi CS, et al. Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Proc Natl Acad Sci U S A 2007; 104(43): 17075-80.
123. Fromenty B, Robin MA, Igoudjil A, Mansouri A, Pessayre D. The ins and outs of mitochondrial dysfunction in NASH. Diabetes Metab 2004; 30(2): 121-38.
124. Matsuzawa-Nagata N, Takamura T, Ando H, et al. Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity. Metabolism 2008; 57(8): 1071-7.
125. Guichard C, Moreau R, Pessayre D, Epperson TK, Krause KH. NOX family NADPH oxidases in liver and in pancreatic islets: a role in the metabolic syndrome and diabetes? Biochem Soc Trans 2008; 36(Pt 5): 920-9.
126. Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 2007; 87(1): 245-313.
127. Carmiel-Haggai M, Cederbaum AI, Nieto N. A high-fat diet leads to the progression of non-alcoholic fatty liver disease in obese rats. Faseb J 2005; 19(1): 136-8.
128. Das K, Kar P. Non-alcoholic steatohepatitis. J Assoc Physicians India 2005; 53: 195-9.
129. Duvnjak M, Lerotic I, Barsic N, Tomasic V, Virovic Jukic L, Velagic V. Pathogenesis and management issues for non-alcoholic fatty liver disease. World J Gastroenterol 2007; 13(34): 4539-50.
130. Nicolson GL. Metabolic syndrome and mitochondrial function: molecular replacement and antioxidant supplements to prevent membrane peroxidation and restore mitochondrial function. J Cell Biochem 2007; 100(6): 1352-69.
131. Malhi H, Gores GJ, Lemasters JJ. Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology 2006; 43(2 Suppl 1): S31-44.
132. Carter-Kent C, Zein NN, Feldstein AE. Cytokines in the pathogenesis of fatty liver and disease progression to steatohepatitis: implications for treatment. Am J Gastroenterol 2008; 103(4): 1036-42.
133. Aubert J, Begriche K, Knockaert L, Robin MA, Fromenty B. Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role. Clin Res Hepatol Gastroenterol 2011; 35(10): 630-7.
134. Schattenberg JM, Wang Y, Singh R, Rigoli RM, Czaja MJ. Hepatocyte CYP2E1 overexpression and steatohepatitis lead to impaired hepatic insulin signaling. J Biol Chem 2005 Mar 18; 280(11): 9887-94.
135. Hoehn KL, Salmon AB, Hohnen-Behrens C, et al. Insulin resistance is a cellular antioxidant defense mechanism. Proc Natl Acad Sci U S A 2009; 106(42): 17787-92.
136. Narasimhan S, Gokulakrishnan K, Sampathkumar R, Farooq S, Ravikumar R, Mohan V, et al. Oxidative stress is independently as sociated with non-alcoholic fatty liver disease (NAFLD) in subjects with and without type 2 diabetes. Clin Biochem 2010; 43(10-11): 815-21.
137. Cotrim HP, Carvalho F, Siqueira AC, Lordelo M, Rocha R, De Freitas LA. Nonalcoholic fatty liver and insulin resistance among petrochemical workers. JAMA 2005; 294(13): 1618-20.
138. Xu Z, Chen L, Leung L, Yen TS, Lee C, Chan JY. Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia. Proc Natl Acad Sci U S A 2005; 102(11): 4120-5.
139. Sookoian S, Rosselli MS, Gemma C, Burgueno AL, Fernandez Gianotti T, Castano GO, et al. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor gamma coactivator 1alpha promoter. Hepatology 2010; 52(6): 1992-2000.
140. Webster BR, Lu Z, Sack MN, Scott I. The role of sirtuins in modulating redox stressors. Free Radic Biol Med 2012; 52(2): 281-90.
141. Yang Y, Fu W, Chen J, et al. SIRT1 sumoylation regulates its deacetylase activity and cellular response to genotoxic stress. Nat Cell Biol 2007; 9(11): 1253-62.
142. Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab 2009; 9(4): 327-38.
143. Gao Z, Zhang J, Kheterpal I, Kennedy N, Davis RJ, Ye J. SIRT1 degradation in response to persistent JNK1 activation contributes to hepatic steatosis in obesity. J Biol Chem 2011 May 3.
144. Minocherhomji S, Tollefsbol TO, Singh KK. Mitochondrial regulation of epigenetics and its role in human diseases. Epigenetics 2012; 7(4).
145. Kim HS, Patel K, Muldoon-Jacobs K, et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 2010; 17(1): 41-52.
146. Scher MB, Vaquero A, Reinberg D. SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress. Genes Dev 2007; 21(8): 920-8.
147. Shimazu T, Hirschey MD, Hua L, et al. SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab 2010; 12(6): 654-61.
148. Hirschey MD, Shimazu T, Goetzman E, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 2010; 464(7285): 121-5.
149. Hirschey MD, Shimazu T, Jing E, et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell 2011; 44(2): 177-90.
150. Hirschey MD, Shimazu T, Capra JA, Pollard KS, Verdin E. SIRT1 and SIRT3 deacetylate homologous substrates: AceCS1,2 and HMGCS1,2. Aging (Albany NY) 2011; 3(6): 635-42.
151. Garinis GA, Fruci B, Mazza A, et al. Metformin versus dietary treatment in nonalcoholic hepatic steatosis: a randomized study. Int J Obes (Lond) 2010; 34(8): 1255-64.
152. Nelson LE, Valentine RJ, Cacicedo JM, Gauthier MS, Ido Y, Ruderman NB. A novel inverse relationship between metformintriggered AMPK-SIRT1 signaling and p53 protein abundance in high glucose exposed HepG2 cells. Am J Physiol Cell Physiol 2010 Feb 29.
153. Gavrilova O, Haluzik M, Matsusue K, et al. Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem 2003; 278(36): 34268-76.
154. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362(18): 1675-85.
155. Shen Z, Liang X, Rogers CQ, Rideout D, You M. Involvement of adiponectin-SIRT1-AMPK signaling in the protective action of rosiglitazone against alcoholic fatty liver in mice. Am J Physiol Gastrointest Liver Physiol 2011; 298(3): G364-74.
156. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356(24): 2457-71.
157. Ryder RE. Pioglitazone and bladder cancer. Lancet 2011; 378(9802): 1544; author reply-5.
158. Zanchi A, Maillard M, Jornayvaz FR, et al. Effects of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone on renal and hormonal responses to salt in diabetic and hypertensive individuals. Diabetologia 2010; 53(8): 1568-75.
159. Anderson N, Borlak J. Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacol Rev 2008; 60(3): 311-57.
160. Valdecantos MP, Perez-Matute P, Gonzalez-Muniesa P, Prieto-Hontoria PL, Moreno-Aliaga MJ, Martinez JA. Lipoic Acid Improves Mitochondrial Function in Nonalcoholic Steatosis Through the Stimulation of Sirtuin 1 and Sirtuin 3. Obesity (Silver Spring) 2012 Feb 13.
161. Roth CL, Elfers CT, Figlewicz DP, et al. Vitamin D deficiency in obese rats exacerbates nonalcoholic fatty liver disease and increases hepatic resistin and Toll-like receptor activation. Hepatology 2012; 55(4): 1103-11.
162. Zelber-Sagi S, Ratziu V, Oren R. Nutrition and physical activity in NAFLD: an overview of the epidemiological evidence. World J Gastroenterol 2011; 17(29): 3377-89.
163. Soory M. Relevance of nutritional antioxidants in metabolic syndrome, ageing and cancer: potential for therapeutic targeting. Infect Disord Drug Targets 2009; 9(4): 400-14.
164. Cho SJ, Jung UJ, Choi MS. Differential effects of low-dose resveratrol on adiposity and hepatic steatosis in diet-induced obese mice. Br J Nutr 2012; 14: 1-10.
165. Gomez-Zorita S, Fernandez-Quintela A, Macarulla MT, et al. Resveratrol attenuates steatosis in obese Zucker rats by decreasing fatty acid availability and reducing oxidative stress. Br J Nutr 2012; 107(2): 202-10.
166. Bujanda L, Hijona E, Larzabal M, et al. Resveratrol inhibits nonalcoholic fatty liver disease in rats. BMC Gastroenterol 2008; 8: 40.