Hepatology International

, Volume 10, Issue 3, pp 394–406 | Cite as

Genetic and epigenetic mechanisms of NASH

Review Article
First Online:
Received:
Accepted:

Abstract

Along with the obesity epidemic, the prevalence of nonalcoholic fatty liver disease (NAFLD) has increased exponentially. The histological disease spectrum of NAFLD ranges from bland fatty liver (hepatic steatosis), to the concomitant presence of inflammation and ballooning which defines nonalcoholic steatohepatitis (NASH). The latter can progress in a subset to fibrosis, leading ultimately to cirrhosis and hepatocellular carcinoma. The past decade has seen tremendous advances in our understanding of the genetic and epigenetic bases of NAFLD, mainly through the application of high end technology platforms including genome-wide association studies (GWAS). These have helped to define common gene variants (minor allele frequency >5 %) that contribute to the NAFLD phenotype. Looking to the future, these discoveries are expected to lead to improved diagnostics, the personalization of medicine, and a better understanding of the pathophysiological underpinnings that drive the transition from NAFLD to steatohepatitis and fibrosis, leading to the identification of novel therapeutic targets. In this review, we summarize data on the current state of knowledge with regard to the genetic and epigenetic mechanisms for the development of NASH.

Keywords

Nonalcoholic steatohepatitis Genetic Epigenetic 
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Notes

Acknowledgements

J. G. is supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney, a National Health and Medical Research Council of Australia (NHMRC) Program Grant (1053206) and Project Grants 1006759 and 1047417. M. E. is supported by an International Postgraduate Research Scholarships (IPRS) and an Australian Postgraduate Award (APA) of the University of Sydney.

Compliance with ethical standards

Ethical approval

This article does not consist of any study on human or animal subjects.

References

  1. 1.
    Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA 2012;307(5):491–497CrossRefPubMedGoogle Scholar
  2. 2.
    Law K, Brunt EM. Nonalcoholic fatty liver disease. Clin Liver Dis 2010;14:591–604CrossRefPubMedGoogle Scholar
  3. 3.
    Contos MJ, Choudhury J, Mills AS, Sanyal AJ. The histologic spectrum of nonalcoholic fatty liver disease. Clin Liver Dis 2004;8:481CrossRefPubMedGoogle Scholar
  4. 4.
    Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011;34(3):274–285CrossRefPubMedGoogle Scholar
  5. 5.
    Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40(12):1461–1465CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Chalasani N, Guo X, Loomba R, Goodarzi MO, Haritunians T, Kwon S, et al. Genome-wide association study identifies variants associated with histologic features of nonalcoholic fatty liver disease. Gastroenterology 2010;139(5):1567–1576, 1576.e1–1576.e6Google Scholar
  7. 7.
    Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 2011;7(3):e1001324CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Sookoian S, Pirola CJ. Meta-analysis of the influence of I148 M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 2011;53(6):1883–1894CrossRefPubMedGoogle Scholar
  9. 9.
    Ballestri S, Day CP, Daly AK. Polymorphism in the farnesyl diphosphate farnesyl transferase 1 gene and nonalcoholic fatty liver disease severity. Gastroenterology 2011;140(5):1694–1695CrossRefPubMedGoogle Scholar
  10. 10.
    Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjærg-Hansen A, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2014;46(4):352–356CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Liu YL, Reeves HL, Burt AD, Tiniakos D, McPherson S, Leathart JB, Allison ME, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun 2014;5:4309PubMedPubMedCentralGoogle Scholar
  12. 12.
    Dongiovanni P, Petta S, Maglio C, Fracanzani AL, Pipitone R, Mozzi E, et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 2015;61:506–514CrossRefPubMedGoogle Scholar
  13. 13.
    Sookoian S, Castaño GO, Scian R, Mallardi P, Fernández Gianotti T, Burgueño AL, et al. Genetic variation in transmembrane 6 superfamily member 2 and the risk of nonalcoholic fatty liver disease and histological disease severity. Hepatology 2015;61(2):515–525CrossRefPubMedGoogle Scholar
  14. 14.
    Wong VW, Wong GL, Tse CH, Chan HL. Prevalence of the TM6SF2 variant and non-alcoholic fatty liver disease in Chinese. J Hepatol 2014;61(3):708–709CrossRefPubMedGoogle Scholar
  15. 15.
    Valenti L, Al-Serri A, Daly AK, Galmozzi E, Rametta R, Dongiovanni P, et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148 M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2010;51(4):1209–1217CrossRefPubMedGoogle Scholar
  16. 16.
    Valenti L, Alisi A, Galmozzi E, Bartuli A, Del Menico B, Alterio A, et al. I148 M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease. Hepatology 2010;52(4):1274–1280CrossRefPubMedGoogle Scholar
  17. 17.
    Rotman Y, Koh C, Zmuda JM, Kleiner DE, Liang TJ, NASH CRN. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 2010;52(3):894–903CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Singal AG, Manjunath H, Yopp AC, Beg MS, Marrero JA, Gopal P, et al. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol 2014;109(3):325–334CrossRefPubMedGoogle Scholar
  19. 19.
    Namikawa C, Shu-Ping Z, Vyselaar JR, Nozaki Y, Nemoto Y, Ono M, et al. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. J Hepatol 2004;40:781–786CrossRefPubMedGoogle Scholar
  20. 20.
    Gambino R, Cassader M, Pagano G, Durazzo M, Musso G. Polymorphism in microsomal triglyceride transfer protein: a link between liver disease and atherogenic postprandial lipid profile in NASH? Hepatology 2007;45:1097–1107CrossRefPubMedGoogle Scholar
  21. 21.
    Song J, da Costa KA, Fischer LM, Kohlmeier M, Kwock L, Wang S, et al. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). FASEB J 2005;19:1266–1271CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Dong H, Wang J, Li C, Hirose A, Nozaki Y, Takahashi M, et al. The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population. J Hepatol 2007;46:915–920CrossRefPubMedGoogle Scholar
  23. 23.
    Valenti L, Nobili V, Al-Serri A, Rametta R, Leathart JB, Zappa MA, et al. The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage independently of PNPLA3 I148 M genotype in patients with nonalcoholic fatty liver. J Hepatol 2011;55:1409–1414CrossRefPubMedGoogle Scholar
  24. 24.
    Sazci A1, Akpinar G, Aygun C, Ergul E, Senturk O, Hulagu S. Association of apolipoprotein E polymorphisms in patients with non-alcoholic steatohepatitis. Dig Dis Sci 2008;53:3218–3224CrossRefPubMedGoogle Scholar
  25. 25.
    Aller R, De Luis DA, Fernandez L, Calle F, Velayos B, Izaola O, et al. Influence of Ala54Thr polymorphism of fatty acid-binding protein 2 on histological alterations and insulin resistance of non alcoholic fatty liver disease. Eur Rev Med Pharmacol 2009;13:357–364Google Scholar
  26. 26.
    Dongiovanni P, Valenti L, Rametta R, Daly AK, Nobili V, Mozzi E, et al. Genetic variants regulating insulin receptor signaling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease. Gut 2010;59:267–273CrossRefPubMedGoogle Scholar
  27. 27.
    Dongiovanni P, Rametta R, Fracanzani AL, et al. Lack of association between peroxisome proliferator-activated receptors alpha and γ2 polymorphisms and progressive liver damage in patients with non-alcoholic fatty liver disease: a case–control study. BMC Gastroenterology 2010;10:102–108CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Domenici FA, Brochado MJ, Martinelli Ade L, Zucoloto S, da Cunha SF, Vannucchi H. Peroxisome proliferator-activated receptors alpha and γ2 polymorphisms in nonalcoholic fatty liver disease: a study in Brazilian patients. Gene 2013;529:326–331CrossRefPubMedGoogle Scholar
  29. 29.
    Yoneda M, Hotta K, Nozaki Y, Endo H, Uchiyama T, Mawatari H, et al. Association between PPARGC1A polymorphisms and the occurrence of nonalcoholic fatty liver disease (NAFLD). BMC Gastroenterol 2008;8:27CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Wong VW, Wong GL, Tsang SW, Hui AY, Chan AW, Choi PC, et al. Genetic polymorphisms of adiponectin and tumor necrosis factor-α and nonalcoholic fatty liver disease in Chinese people. J Gastroenterol Hepatol 2008;23:914–921CrossRefPubMedGoogle Scholar
  31. 31.
    Gupta AC, Misra R, Sakhuja P, Singh Y, Basir SF, Sarin SK. Association of adiponectin gene functional polymorphisms (−11377C/G and +45T/G) with nonalcoholic fatty liver disease. Gene 2012;496:63–67CrossRefPubMedGoogle Scholar
  32. 32.
    Zain SM, Mohamed Z, Mahadeva S, Cheah PL, Rampal S, Chin KF, et al. Impact of leptin receptor gene variants on risk of non-alcoholic fatty liver disease and its interaction with adiponutrin gene. J Gastroenterol Hepatol 2013;28:873–879CrossRefPubMedGoogle Scholar
  33. 33.
    Petta S, Grimaudo S, Cammà C, Cabibi D, Di Marco V, Licata G, et al. IL28B and PNPLA3 polymorphisms affect histological liver damage in patients with non-alcoholic fatty liver disease. J Hepatol 2012;56:1356–1362CrossRefPubMedGoogle Scholar
  34. 34.
    Eslam M, Hashem AM, Leung R, Romero-Gomez M, Berg T, Dore GJ, et al. Interferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease. Nat Commun 2015;6:6422CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Kiziltas S, Ata P, Colak Y, Mesçi B, Senates E, Enc F, et al. TLR4 gene polymorphism in patients with nonalcoholic fatty liver disease in comparison to healthy controls. Metab Syndr Relat Disord 2014;12:165–170CrossRefPubMedGoogle Scholar
  36. 36.
    Valenti L, Fracanzani AL, Dongiovanni P, Santorelli G, Branchi A, Taioli E, et al. Tumor necrosis factor α promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease. Gastroenterology 2002;122:274–280CrossRefPubMedGoogle Scholar
  37. 37.
    Tokushige K, Takakura M, Tsuchiya-Matsushita N, Taniai M, Hashimoto E, Shiratori K. Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis. J Hepatol 2007;46:1104–1110CrossRefPubMedGoogle Scholar
  38. 38.
    Yan X, Xu L, Qi J, Liang X, Ma C, Guo C, et al. sTRAIL levels and TRAIL gene polymorphisms in Chinese patients with fatty liver disease. Immunogenetics 2009;61(8):551–556CrossRefPubMedGoogle Scholar
  39. 39.
    Carulli L, Canedi I, Rondinella S, Lombardini S, Ganazzi D, Fargion S, et al. Genetic polymorphisms in non-alcoholic fatty liver disease: interleukin-6-174G/C polymorphism is associated with non-alcoholic steatohepatitis. Dig Liver Dis 2009;41(11):823–8Google Scholar
  40. 40.
    Nozaki Y, Saibara T, Nemoto Y, Ono M, Akisawa N, Iwasaki S, et al. Polymorphisms of interleukin-1 β and β 3-adrenergic receptor in Japanese patients with nonalcoholic steatohepatitis. Alcohol Clin Exp Res 2004;28:106S–1010SPubMedGoogle Scholar
  41. 41.
    Brun P, Castagliuolo I, Floreani AR, Buda A, Blasone L, Palù G, et al. Increased risk of NASH in patients carrying the C(-159)T polymorphism in the CD14 gene promoter region. Gut 2006;55:1212CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Dixon JB, Bhathal PS, Jonsson JR, Dixon AF, Powell EE, O'Brien PE. Pro-fibrotic polymorphisms predictive of advanced liver fibrosis in the severely obese. J Hepatol 2003;39:967–971CrossRefPubMedGoogle Scholar
  43. 43.
    Yoneda M, Hotta K, Nozaki Y, Endo H, Uchiyama T, Mawatari H, et al. Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease. Liver Int 2009;29:1078–1085CrossRefPubMedGoogle Scholar
  44. 44.
    Wood KL, Miller MH, Dillon JF. Systematic review of genetic association studies involving histologically confirmed non-alcoholic fatty liver disease. BMJ Open Gastroenterol 2015;2(1):e000019CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Tian C, Stokowski RP, Kershenobich D, Ballinger DG, Hinds DA. Variant in PNPLA3 is associated with alcoholic liver disease. Nat Genet 2010;42:21–23CrossRefPubMedGoogle Scholar
  46. 46.
    Santoro N, Kursawe R, D’Adamo E, Dykas DJ, Zhang CK, Bale AE, et al. A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology 2010;52:1281–1290CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Burza MA, Pirazzi C, Maglio C, Sjöholm K, Mancina RM, Svensson PA, et al. PNPLA3 I148 M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals. Dig Liver Dis 2012;44(12):1037–1041CrossRefPubMedGoogle Scholar
  48. 48.
    Davis JN, Lê KA, Walker RW, Vikman S, Spruijt-Metz D, Weigensberg MJ, et al. Increased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption. Am J Clin Nutr 2010;92:1522–1527CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Santoro N, Savoye M, Kim G, Marotto K, Shaw MM, Pierpont B, et al. Hepatic fat accumulation is modulated by the interaction between the rs738409 variant in the PNPLA3 gene and the dietary omega6/omega3 PUFA intake. PLoS ONE 2012;7:e37827CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015;149(2):367–78Google Scholar
  51. 51.
    Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology 2015;149(2):379–88Google Scholar
  52. 52.
    Sevastianova K, Kotronen A, Gastaldelli A, Perttilä J, Hakkarainen A, Lundbom J, et al. Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss-induced decrease in liver fat in humans. Am J Clin Nutr 2011;94(1):104–111CrossRefPubMedGoogle Scholar
  53. 53.
    Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362(18):1675–1685CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015;385(9972):956–965CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Armstrong MJ, Gaunt P, Aithal GP, Parker R, Barton D, Hull D, et al. Liraglutide is effective in the histological clearance of non-alcoholic steatohepatitis in a multicentre, doubleblinded, randomised, placebo-controlled phase II trial. J Hepatol 2015;62:S187CrossRefGoogle Scholar
  56. 56.
    Dongiovanni P, Petta S, Mannisto V, Margherita Mancina R, Pipitone R, Karja V, et al. Statin use and nonalcoholic steatohepatitis in at risk individuals. J Hepatol 2015;63(3):705–12Google Scholar
  57. 57.
    He S, McPhaul C, Li JZ, Garuti R, Kinch L, Grishin NV, et al. A sequence variation (I148 M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem 2010;285:6706–6715CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Huang Y, Cohen JC, Hobbs HH. Expression and characterization of a PNPLA3 protein isoform (I148 M) associated with nonalcoholic fatty liver disease. J Biol Chem 2011;286:37085–37093CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Chen W, Chang B, Li L, Chan L. Patatin-like phospholipase domain-containing 3/adiponutrin deficiency in mice is not associated with fatty liver disease. Hepatology 2010;52:1134–1142CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Basantani MK, Sitnick MT, Cai L, Brenner DS, Gardner NP, Li JZ, et al. Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. J Lipid Res 2011;52:318–329CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Smagris E, BasuRay S, Li J, Huang Y, Lai KM, Gromada J, et al. Pnpla3I148 M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 2015;61(1):108–118CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Pirazzi C, Valenti L, Motta BM, Pingitore P, Hedfalk K, Mancina RM, et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum Mol Genet 2014;23:4077–4085CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Mahdessian H, Taxiarchis A, Popov S, Silveira A, Franco-Cereceda A, Hamsten A, et al. TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content. Proc Natl Acad Sci USA 2014;111:8913–8918CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Steenbergen RH, Joyce MA, Thomas BS, Jones D, Law J, Russell R, et al. Human serum leads to differentiation of human hepatoma cells, restoration of very-low-density lipoprotein secretion, and a 1000-fold increase in HCV Japanese fulminant hepatitis type 1 titers. Hepatology 2013;58(6):1907–1917CrossRefPubMedGoogle Scholar
  65. 65.
    Meex SJ, Andreo U, Sparks JD, Fisher EA. Huh-7 or HepG2 cells: which is the better model for studying human apolipoprotein-B100 assembly and secretion? J Lipid Res 2011;52(1):152–158CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Stranger BE, Stahl EA, Raj T. Progress and promise of genome-wide association studies for human complex trait genetics. Genetics 2011;187(2):367–383CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, et al. Global variation in copy number in the human genome. Nature 2006;444(7118):444–454CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Zain SM, Mohamed R, Cooper DN, Razali R, Rampal S, Mahadeva S, et al. Genome-wide analysis of copy number variation identifies candidate gene loci associated with the progression of non-alcoholic fatty liver disease. PLoS ONE 2014;9(4):e95604CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 2005;438:685–689CrossRefPubMedGoogle Scholar
  70. 70.
    Kozomara A, Griffiths-Jones S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucl Acids Res 2011;39:D152–D157CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Cermelli S, Ruggieri A, Marrero JA, Ioannou GN, Beretta L. Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS ONE 2011;6:e23937CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Zhang Y, Cheng X, Lu Z, Wang J, Chen H, Fan W, et al. Upregulation of miR-15b in NAFLD models and in the serum of patients with fatty liver disease. Diabetes Res Clin Pract 2013;99:327–334CrossRefPubMedGoogle Scholar
  73. 73.
    Pirola CJ, Fernández Gianotti T, Castaño GO, Mallardi P, San Martino J, Mora Gonzalez Lopez Ledesma M, et al. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut 2015;64(5):800–812CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Cheung O, Puri P, Eicken C, Contos MJ, Mirshahi F, Maher JW, et al. Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression. Hepatology 2008;48(6):1810–1820CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 2006;3:87–98CrossRefPubMedGoogle Scholar
  76. 76.
    Hsu SH, Wang B, Kota J, Yu J, Costinean S, Kutay H, et al. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J Clin Invest 2012;122(8):2871–2883CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Tsai WC, Hsu SD, Hsu CS, Lai TC, Chen SJ, Shen R, et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest 2012;122(8):2884–2897CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Cordero P, Campion J, Milagro FI, Martinez JA. Transcriptomic and epigenetic changes in early liver steatosis associated to obesity: effect of dietary methyl donor supplementation. Mol Genet Metab 2013;110(3):388–395CrossRefPubMedGoogle Scholar
  79. 79.
    Sie KK, Li J, Ly A, Sohn KJ, Croxford R, Kim YI. Effect of maternal and postweaning folic acid supplementation on global and gene-specific DNA methylation in the liver of the rat offspring. Mol Nutr Food Res 2013;57(4):677–685CrossRefPubMedGoogle Scholar
  80. 80.
    Cordero P, Campion J, Milagro FI, Martinez JA. Dietary supplementation with methyl donor groups could prevent nonalcoholic fatty liver. Hepatology 2011;53:2151–2152CrossRefPubMedGoogle Scholar
  81. 81.
    Ahrens M, Ammerpohl O, von Schönfels W, Kolarova J, Bens S, Itzel T, et al. DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. Cell Metab 2013;18(2):296–302CrossRefPubMedGoogle Scholar
  82. 82.
    Sookoian S, Rosselli MS, Gemma C, Burgueño AL, Fernández Gianotti T, Castaño GO, et al. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter. Hepatology 2010;52:1992–2000CrossRefPubMedGoogle Scholar
  83. 83.
    Pirola CJ, Gianotti TF, Burgueño AL, Rey-Funes M, Loidl CF, Mallardi P, et al. Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut 2013;62:1356–1363CrossRefPubMedGoogle Scholar
  84. 84.
    Murphy SK, Yang H, Moylan CA, Pang H, Dellinger A, Abdelmalek MF, et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology 2013;145(5):1076–1087CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Zeybel M, Hardy T, Robinson SM, Fox C, Anstee QM, Ness T, et al. Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease. Clin Epigenet 2015;7(1):25CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Chen ZJ, Pikaard CS. Epigenetic silencing of RNA polymerase I transcription: a role for DNA methylation and histone modification in nucleolar dominance. Genes Dev 1997;11:2124–2136. doi: 10.1101/gad.11.16.2124 CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Grunstein M. Histone acetylation in chromatin structure and transcription. Nature 1997;389:349–352. doi: 10.1038/38664 CrossRefPubMedGoogle Scholar
  88. 88.
    Aagaard-Tillery KM, Grove K, Bishop J, Ke X, Fu Q, McKnight R, et al. Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome. J Mol Endocrinol 2008;41(2):91–102CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Jun HJ, Kim J, Hoang MH, Lee SJ. Hepatic lipid accumulation alters global histone h3 lysine 9 and 4 trimethylation in the peroxisome proliferator-activated receptor alpha network. PLoS ONE 2012;7(9):e44345CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Bricambert J, Miranda J, Benhamed F, Girard J, Postic C, Dentin R. Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice. J Clin Invest 2010;120(12):4316–4331CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Cao Y, Xue Y, Xue L, Jiang X, Wang X, Zhang Z, et al. Hepatic menin recruits SIRT1 to control liver steatosis through histone deacetylation. J Hepatol 2013;59(6):1299–1306CrossRefPubMedGoogle Scholar
  92. 92.
    Kim HS, Xiao C, Wang RH, Lahusen T, Xu X, Vassilopoulos A, et al. Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metab 2010;12(3):224–236CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Yoshizawa T, Karim MF, Sato Y, Senokuchi T, Miyata K, Fukuda T, et al. SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway. Cell Metab 2014;19(4):712–721CrossRefPubMedGoogle Scholar
  94. 94.
    Alenghat T, Meyers K, Mullican SE, Leitner K, Adeniji-Adele A, Avila J, et al. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 2008;456(7224):997–1000CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Feng D, Liu T, Sun Z, Bugge A, Mullican SE, Alenghat T, et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 2011;331(6022):1315–1319CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Bhaskara S, Knutson SK, Jiang G, Chandrasekharan MB, Wilson AJ, Zheng S, et al. Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 2010;18(5):436–447CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Tian Y, Wong VW, Wong GL, Yang W, Sun H, Shen J, et al. Histone deacetylase HDAC8 promotes insulin resistance and β-catenin activation in NAFLD-associated hepatocellular carcinoma. Cancer Res. 2015;75(22):4803–16Google Scholar
  98. 98.
    Tian Y, Wong VW, Chan HL, Cheng AS. Epigenetic regulation of hepatocellular carcinoma in non-alcoholic fatty liver disease. Semin Cancer Biol 2013;23:471–482CrossRefPubMedGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2015

Authors and Affiliations

  1. 1.Storr Liver Centre, Westmead Millennium Institute, Westmead HospitalUniversity of SydneySydneyAustralia
  2. 2.Department of MedicineWestmead HospitalWestmeadAustralia

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