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The Genetics of Nonalcoholic Fatty Liver Disease: Role of Diet as a Modifying Factor

  • Genetics (GVZ Dedoussis, Section Editor)
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Abstract

Nonalcoholic fatty liver disease (NAFLD) is defined as the hepatic manifestation of the metabolic syndrome, and thus it is mainly linked to excess body weight and systematic insulin resistance. Moreover, recently published data are indicative of the contribution of environmental factors and susceptible genetic background in NAFLD onset and progression. PNPLA3 rs738409 is the main variant studied for NAFLD so far, and diet is recognized as the drastic environmental exposure. Research on the field is preliminary but promising. This review meets the need of a summary of all available data; it describes the role of specific genes and dietary constituents, as well as the nutrigenomic and nutrigenetic effects on NAFLD. Studies in the area hold promise for future personalized diet interventions on the reduction of NAFLD and related health problems incidence.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10(11):686–90.

    CAS  PubMed  Google Scholar 

  2. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52(5):1836–46.

    CAS  PubMed  Google Scholar 

  3. Bellentani S et al. The epidemiology of fatty liver. Eur J Gastroenterol Hepatol. 2004;16(11):1087–93.

    PubMed  Google Scholar 

  4. Struben VM, Hespenheide EE, Caldwell SH. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. Am J Med. 2000;108(1):9–13.

    CAS  PubMed  Google Scholar 

  5. Schwimmer JB et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology. 2009;136(5):1585–92.

    PubMed Central  PubMed  Google Scholar 

  6. Makkonen J et al. Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: a study in monozygotic and dizygotic twins. J Hepatol. 2009;50(5):1035–42.

    CAS  PubMed  Google Scholar 

  7. Anstee QM, Day CP. The genetics of NAFLD. Nat Rev Gastroenterol Hepatol. 2013;10(11):645–55.

    CAS  PubMed  Google Scholar 

  8. Huang Y et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci U S A. 2010;107(17):7892–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Romeo S et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40(12):1461–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Yuan X et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet. 2008;83(4):520–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Valenti L et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51(4):1209–17.

    CAS  PubMed  Google Scholar 

  12. Sookoian S et al. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J Lipid Res. 2009;50(10):2111–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Rotman Y et al. 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):894–903.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Li Y, Li XH, Yuan H. Angiotensin II type-2 receptor-specific effects on the cardiovascular system. Cardiovasc Diagn Ther. 2012;2(1):56–62.

    PubMed Central  PubMed  Google Scholar 

  15. Dupuis J et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet. 2010;42(2):105–16.

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Speliotes EK 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):e1001324.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Chambers JC et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet. 2011;43(11):1131–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Beer NL et al. The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum Mol Genet. 2009;18(21):4081–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Petta S et al. Glucokinase regulatory protein gene polymorphism affects liver fibrosis in non-alcoholic Fatty liver disease. PLoS One. 2014;9(2):e87523.

    PubMed Central  PubMed  Google Scholar 

  20. Santoro N et al. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology. 2012;55(3):781–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Valenti L, Alisi A, Nobili V. Unraveling the genetics of fatty liver in obese children: additive effect of P446L GCKR and I148M PNPLA3 polymorphisms. Hepatology. 2012;55(3):661–3.

    PubMed  Google Scholar 

  22. Tan HL, et al. Association of glucokinase regulatory gene polymorphisms with risk and severity of non-alcoholic fatty liver disease: an interaction study with adiponutrin gene. J Gastroenterol 2013. doi:10.1007/s00535-013-0850-x.

  23. Lin YC et al. Genetic variants in GCKR and PNPLA3 confer susceptibility to nonalcoholic fatty liver disease in obese individuals. Am J Clin Nutr. 2014;99(4):869–74.

    CAS  PubMed  Google Scholar 

  24. Nettleton JA et al. Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies. Diabetes Care. 2010;33(12):2684–91.

    PubMed Central  PubMed  Google Scholar 

  25. Oakley F et al. Angiotensin II activates I kappaB kinase phosphorylation of RelA at Ser 536 to promote myofibroblast survival and liver fibrosis. Gastroenterology. 2009;136(7):2334–2344 e1.

    CAS  PubMed  Google Scholar 

  26. Li X et al. Angiotensin II and Aldosterone stimulating NF-kappaB and AP-1 activation in hepatic fibrosis of rat. Regul Pept. 2007;138(1):15–25.

    CAS  PubMed  Google Scholar 

  27. Wei Y et al. Angiotensin II-induced non-alcoholic fatty liver disease is mediated by oxidative stress in transgenic TG(mRen2)27(Ren2) rats. J Hepatol. 2008;49(3):417–28.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Moreno M et al. Reduction of advanced liver fibrosis by short-term targeted delivery of an angiotensin receptor blocker to hepatic stellate cells in rats. Hepatology. 2010;51(3):942–52.

    CAS  PubMed  Google Scholar 

  29. Yoneda M et al. Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease. Liver Int. 2009;29(7):1078–85.

    CAS  PubMed  Google Scholar 

  30. Zain SM et al. Susceptibility and gene interaction study of the angiotensin II type 1 receptor (AGTR1) gene polymorphisms with non-alcoholic fatty liver disease in a multi-ethnic population. PLoS One. 2013;8(3):e58538.

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Dongiovanni P, Anstee QM, Valenti L. Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment. Curr Pharm Des. 2013;19(29):5219–38.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Namikawa C et al. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. J Hepatol. 2004;40(5):781–6.

    CAS  PubMed  Google Scholar 

  33. Gambino R et al. Polymorphism in microsomal triglyceride transfer protein: a link between liver disease and atherogenic postprandial lipid profile in NASH? Hepatology. 2007;45(5):1097–107.

    CAS  PubMed  Google Scholar 

  34. Song J et al. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). FASEB J. 2005;19(10):1266–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Dong H et al. The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population. J Hepatol. 2007;46(5):915–20.

    CAS  PubMed  Google Scholar 

  36. Romeo S, Cohen JC, Hobbs HH. No association between polymorphism in PEMT (V175M) and hepatic triglyceride content in the Dallas Heart Study. FASEB J. 2006;20(12):2180. author reply 2181-2.

    CAS  PubMed  Google Scholar 

  37. Petersen KF et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med. 2010;362(12):1082–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Verrijken A et al. A gene variant of PNPLA3, but not of APOC3, is associated with histological parameters of NAFLD in an obese population. Obesity (Silver Spring). 2013;21(10):2138–45.

    CAS  Google Scholar 

  39. Zampino R et al. Abdominal fat interacts with PNPLA3 I148M, but not with the APOC3 variant in the pathogenesis of liver steatosis in chronic hepatitis C. J Viral Hepat. 2013;20(8):517–23.

    CAS  PubMed  Google Scholar 

  40. Valenti L et al. The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage independently of PNPLA3 I148M genotype in patients with nonalcoholic fatty liver. J Hepatol. 2011;55(6):1409–14.

    CAS  PubMed  Google Scholar 

  41. Sentinelli F et al. Lack of effect of apolipoprotein C3 polymorphisms on indices of liver steatosis, lipid profile and insulin resistance in obese Southern Europeans. Lipids Health Dis. 2011;10:93.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Al-Serri A et al. The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case-control and intra-familial allele association studies. J Hepatol. 2012;56(2):448–54.

    CAS  PubMed  Google Scholar 

  43. Miele L et al. The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease. Gastroenterology. 2008;135(1):282–291 e1.

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Bechmann LP et al. Glucokinase links Kruppel-like factor 6 to the regulation of hepatic insulin sensitivity in nonalcoholic fatty liver disease. Hepatology. 2012;55(4):1083–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Kozlitina J et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2014;46(4):352–6.

    CAS  PubMed  Google Scholar 

  46. Gerhard GS et al. Next-generation sequence analysis of genes associated with obesity and nonalcoholic fatty liver disease-related cirrhosis in extreme obesity. Hum Hered. 2013;75(2–4):144–51.

    CAS  PubMed  Google Scholar 

  47. Petta S, Muratore C, Craxi A. Non-alcoholic fatty liver disease pathogenesis: the present and the future. Dig Liver Dis. 2009;41(9):615–25.

    CAS  PubMed  Google Scholar 

  48. Thoma C, Day CP, Trenell MI. Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: a systematic review. J Hepatol. 2012;56(1):255–66.

    PubMed  Google Scholar 

  49. Powell LM, Nguyen BT. Fast-food and full-service restaurant consumption among children and adolescents: effect on energy, beverage, and nutrient intake. JAMA Pediatr. 2013;167(1):14–20.

    PubMed Central  PubMed  Google Scholar 

  50. Pereira MA et al. Fast-food habits, weight gain, and insulin resistance (the CARDIA study): 15-year prospective analysis. Lancet. 2005;365(9453):36–42.

    PubMed  Google Scholar 

  51. Kechagias S et al. Fast-food-based hyper-alimentation can induce rapid and profound elevation of serum alanine aminotransferase in healthy subjects. Gut. 2008;57(5):649–54.

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Charlton M et al. Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol. 2011;301(5):G825–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Brownell KD et al. The public health and economic benefits of taxing sugar-sweetened beverages. N Engl J Med. 2009;361(16):1599–605.

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Ouyang X et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008;48(6):993–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Lim JS et al. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol. 2010;7(5):251–64.

    CAS  PubMed  Google Scholar 

  56. Stanhope KL, Havel PJ. Fructose consumption: considerations for future research on its effects on adipose distribution, lipid metabolism, and insulin sensitivity in humans. J Nutr. 2009;139(6):1236S–41.

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Chiu S et al. Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials. Eur J Clin Nutr. 2014;68(4):416–23.

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Sathiaraj E et al. A case-control study on nutritional risk factors in non-alcoholic fatty liver disease in Indian population. Eur J Clin Nutr. 2011;65(4):533–7.

    CAS  PubMed  Google Scholar 

  59. Vilar L et al. High-fat diet: a trigger of non-alcoholic steatohepatitis? Preliminary findings in obese subjects. Nutrition. 2008;24(11–12):1097–102.

    CAS  PubMed  Google Scholar 

  60. Musso G et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology. 2003;37(4):909–16.

    CAS  PubMed  Google Scholar 

  61. Donnelly KL et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343–51.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Wang D, Wei Y, Pagliassotti MJ. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology. 2006;147(2):943–51.

    CAS  PubMed  Google Scholar 

  63. Gentile CL, Pagliassotti MJ. The role of fatty acids in the development and progression of nonalcoholic fatty liver disease. J Nutr Biochem. 2008;19(9):567–76.

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Salter AM. Dietary fatty acids and cardiovascular disease. Animal. 2013;7 Suppl 1:163–71.

    CAS  PubMed  Google Scholar 

  65. Ferolla SM et al. Dietary patterns in Brazilian patients with nonalcoholic fatty liver disease: a cross-sectional study. Clinics (Sao Paulo). 2013;68(1):11–7.

    Google Scholar 

  66. Cortez-Pinto H et al. How different is the dietary pattern in non-alcoholic steatohepatitis patients? Clin Nutr. 2006;25(5):816–23.

    CAS  PubMed  Google Scholar 

  67. Zelber-Sagi S et al. Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study. J Hepatol. 2007;47(5):711–7.

    CAS  PubMed  Google Scholar 

  68. Alonso A, Ruiz-Gutierrez V, Martinez-Gonzalez MA. Monounsaturated fatty acids, olive oil and blood pressure: epidemiological, clinical and experimental evidence. Public Health Nutr. 2006;9(2):251–7.

    PubMed  Google Scholar 

  69. Fito M et al. Effect of a traditional Mediterranean diet on lipoprotein oxidation: a randomized controlled trial. Arch Intern Med. 2007;167(11):1195–203.

    PubMed  Google Scholar 

  70. Paniagua JA et al. A MUFA-rich diet improves posprandial glucose, lipid and GLP-1 responses in insulin-resistant subjects. J Am Coll Nutr. 2007;26(5):434–44.

    CAS  PubMed  Google Scholar 

  71. Hussein O et al. Monounsaturated fat decreases hepatic lipid content in non-alcoholic fatty liver disease in rats. World J Gastroenterol. 2007;13(3):361–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Mouzaki M, Allard JP. The role of nutrients in the development, progression, and treatment of nonalcoholic fatty liver disease. J Clin Gastroenterol. 2012;46(6):457–67.

    PubMed  Google Scholar 

  73. Marsman HA et al. Reversal of hepatic steatosis by omega-3 fatty acids measured non-invasively by (1) H-magnetic resonance spectroscopy in a rat model. J Gastroenterol Hepatol. 2011;26(2):356–63.

    CAS  PubMed  Google Scholar 

  74. Ishii H et al. Eicosapentaenoic acid ameliorates steatohepatitis and hepatocellular carcinoma in hepatocyte-specific Pten-deficient mice. J Hepatol. 2009;50(3):562–71.

    CAS  PubMed  Google Scholar 

  75. Gonzalez-Periz A et al. Obesity-induced insulin resistance and hepatic steatosis are alleviated by omega-3 fatty acids: a role for resolvins and protectins. FASEB J. 2009;23(6):1946–57.

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Parker HM et al. Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol. 2012;56(4):944–51.

    CAS  PubMed  Google Scholar 

  77. Bhardwaj S, Passi SJ, Misra A. Overview of trans fatty acids: biochemistry and health effects. Diabetes Metab Syndr. 2011;5(3):161–4.

    PubMed  Google Scholar 

  78. Tetri LH et al. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am J Physiol Gastrointest Liver Physiol. 2008;295(5):G987–95.

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Machado RM et al. Intake of trans fatty acids causes nonalcoholic steatohepatitis and reduces adipose tissue fat content. J Nutr. 2010;140(6):1127–32.

    CAS  PubMed  Google Scholar 

  80. Bezerra Duarte SM et al. Hypocaloric high-protein diet improves clinical and biochemical markers in patients with nonalcoholic fatty liver disease (NAFLD). Nutr Hosp. 2014;29(1):94–101.

    PubMed  Google Scholar 

  81. Tovar AR, Torres N. The role of dietary protein on lipotoxicity. Biochim Biophys Acta. 2010;1801(3):367–71.

    CAS  PubMed  Google Scholar 

  82. Xiao CW et al. Dietary supplementation with soy isoflavones or replacement with soy proteins prevents hepatic lipid droplet accumulation and alters expression of genes involved in lipid metabolism in rats. Genes Nutr. 2014;9(1):373.

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Ricci G et al. Nutrient intake in Italian obese patients: relationships with insulin resistance and markers of non-alcoholic fatty liver disease. Nutrition. 2011;27(6):672–6.

    CAS  PubMed  Google Scholar 

  84. Schugar RC, Crawford PA. Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metab Care. 2012;15(4):374–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Erhardt A et al. Plasma levels of vitamin E and carotenoids are decreased in patients with Nonalcoholic Steatohepatitis (NASH). Eur J Med Res. 2011;16(2):76–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Lavine JE et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305(16):1659–68.

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Sanyal AJ et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675–85.

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Schurks M et al. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ. 2010;341:c5702.

    PubMed Central  PubMed  Google Scholar 

  89. Klein EA et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306(14):1549–56.

    CAS  PubMed  Google Scholar 

  90. Gerss J, Kopcke W. The questionable association of vitamin E supplementation and mortality–inconsistent results of different meta-analytic approaches. Cell Mol Biol (Noisy-le-grand). 2009;55(Suppl):OL1111–20.

    CAS  Google Scholar 

  91. Miller 3rd ER et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142(1):37–46.

    CAS  PubMed  Google Scholar 

  92. Black LJ, et al. Low serum 25-hydroxyvitamin D concentrations are associated with non-alcoholic fatty liver disease in adolescents independent of adiposity. J Gastroenterol Hepatol. 2014;29(6):1215--22.

  93. Targher G et al. Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis. 2007;17(7):517–24.

    CAS  PubMed  Google Scholar 

  94. Pittas AG et al. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab. 2007;92(6):2017–29.

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Kendrick J et al. 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey. Atherosclerosis. 2009;205(1):255–60.

    CAS  PubMed  Google Scholar 

  96. 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.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Fischer LM et al. Sex and menopausal status influence human dietary requirements for the nutrient choline. Am J Clin Nutr. 2007;85(5):1275–85.

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Kohlmeier M et al. Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans. Proc Natl Acad Sci U S A. 2005;102(44):16025–30.

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Ross AB et al. Increasing whole grain intake as part of prevention and treatment of nonalcoholic Fatty liver disease. Int J Endocrinol. 2013;2013:585876.

    PubMed Central  PubMed  Google Scholar 

  100. Ye EQ et al. Greater whole-grain intake is associated with lower risk of type 2 diabetes, cardiovascular disease, and weight gain. J Nutr. 2012;142(7):1304–13.

    CAS  PubMed  Google Scholar 

  101. Georgoulis M et al. The impact of cereal grain consumption on the development and severity of non-alcoholic fatty liver disease. Eur J Nutr 2014. doi:10.1007/s00394-014-0679-y.

  102. Yasutake K et al. Nutritional investigation of non-obese patients with non-alcoholic fatty liver disease: the significance of dietary cholesterol. Scand J Gastroenterol. 2009;44(4):471–7.

    CAS  PubMed  Google Scholar 

  103. Wouters K et al. Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis. Hepatology. 2008;48(2):474–86.

    PubMed  Google Scholar 

  104. Matsuzawa N et al. Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatology. 2007;46(5):1392–403.

    CAS  PubMed  Google Scholar 

  105. Molloy JW et al. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology. 2012;55(2):429–36.

    CAS  PubMed  Google Scholar 

  106. Birerdinc A et al. Caffeine is protective in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2012;35(1):76–82.

    CAS  PubMed  Google Scholar 

  107. Dunn W et al. Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). J Hepatol. 2012;57(2):384–91.

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Gentile CL et al. Experimental evidence for therapeutic potential of taurine in the treatment of nonalcoholic fatty liver disease. Am J Physiol Regul Integr Comp Physiol. 2011;301(6):R1710–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Valenti L et al. Dietary anthocyanins as nutritional therapy for nonalcoholic fatty liver disease. Oxid Med Cell Longev. 2013;2013:145421.

    PubMed Central  PubMed  Google Scholar 

  110. Masterjohn C, Bruno RS. Therapeutic potential of green tea in nonalcoholic fatty liver disease. Nutr Rev. 2012;70(1):41–56.

    PubMed  Google Scholar 

  111. Miele L et al. A case-control study on the effect of metabolic gene polymorphisms, nutrition, and their interaction on the risk of non-alcoholic fatty liver disease. Genes Nutr. 2014;9(2):383. This study is the first case-control study reporting gene-diet interactions in the adult NAFLD population.

    PubMed Central  PubMed  Google Scholar 

  112. Partridge CG et al. The effect of dietary fat intake on hepatic gene expression in LG/J AND SM/J mice. BMC Genomics. 2014;15:99.

    PubMed Central  PubMed  Google Scholar 

  113. Waller-Evans H et al. Nutrigenomics of high fat diet induced obesity in mice suggests relationships between susceptibility to fatty liver disease and the proteasome. PLoS One. 2013;8(12):e82825.

    PubMed Central  PubMed  Google Scholar 

  114. Pruis MG et al. Maternal western diet primes non-alcoholic fatty liver disease in adult mouse offspring. Acta Physiol (Oxf). 2014;210(1):215–27.

    CAS  Google Scholar 

  115. Gabele E et al. A new model of interactive effects of alcohol and high-fat diet on hepatic fibrosis. Alcohol Clin Exp Res. 2011;35(7):1361–7.

    PubMed  Google Scholar 

  116. Santoro N 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(5):e37827. This article presents the interaction between the novel PNPLA3 polymorphism and the type of dietary fat in multiethnic NAFLD adolescent patients.

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Nobili V et al. The I148M variant of PNPLA3 reduces the response to docosahexaenoic acid in children with non-alcoholic fatty liver disease. J Med Food. 2013;16(10):957–60. This article presents the effect of a N-3 supplementation in NAFLD under a specific genetic background.

    CAS  PubMed  Google Scholar 

  118. Schmitz G, Ecker J. The opposing effects of n-3 and n-6 fatty acids. Prog Lipid Res. 2008;47(2):147–55.

    CAS  PubMed  Google Scholar 

  119. Pettinelli P 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.

    CAS  PubMed  Google Scholar 

  120. Kajikawa S et al. Highly purified eicosapentaenoic acid prevents the progression of hepatic steatosis by repressing monounsaturated fatty acid synthesis in high-fat/high-sucrose diet-fed mice. Prostaglandins Leukot Essent Fat Acids. 2009;80(4):229–38.

    CAS  Google Scholar 

  121. Spadaro L et al. 2008. Dig Liver Dis. 2008;40(3):194–9. This study showed a reduction in fatty liver parameters in patients supplemented with n-3 polyunsaturated fatty acids.

    CAS  PubMed  Google Scholar 

  122. Davis JN 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(6):1522–7. This article presents the interaction between the novel PNPLA3 polymorphism and carbohydrates in NAFLD.

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Nobili V et al. Influence of dietary pattern, physical activity, and I148M PNPLA3 on steatosis severity in at-risk adolescents. Genes Nutr. 2014;9(3):392. This article presents the interaction between the novel PNPLA3 polymorphism and specific food groups in NAFLD.

    PubMed Central  PubMed  Google Scholar 

  124. Perttila J et al. PNPLA3 is regulated by glucose in human hepatocytes, and its I148M mutant slows down triglyceride hydrolysis. Am J Physiol Endocrinol Metab. 2012;302(9):E1063–9.

    CAS  PubMed  Google Scholar 

  125. Roglans N et al. Impairment of hepatic Stat-3 activation and reduction of PPARalpha activity in fructose-fed rats. Hepatology. 2007;45(3):778–88.

    CAS  PubMed  Google Scholar 

  126. Ishimoto T et al. Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice. Proc Natl Acad Sci U S A. 2012;109(11):4320–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Sevastianova K 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):104–11.

    CAS  PubMed  Google Scholar 

  128. Garcia-Caraballo SC et al. Prevention and reversal of hepatic steatosis with a high-protein diet in mice. Biochim Biophys Acta. 2013;1832(5):685–95.

    CAS  PubMed  Google Scholar 

  129. Tomita K et al. p53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice. J Hepatol. 2012;57(4):837–43.

    CAS  PubMed  Google Scholar 

  130. Bian EB et al. DNMT1-mediated PTEN hypermethylation confers hepatic stellate cell activation and liver fibrogenesis in rats. Toxicol Appl Pharmacol. 2012;264(1):13–22.

    CAS  PubMed  Google Scholar 

  131. Koca SS et al. The treatment with antibody of TNF-alpha reduces the inflammation, necrosis and fibrosis in the non-alcoholic steatohepatitis induced by methionine- and choline-deficient diet. Inflammation. 2008;31(2):91–8.

    CAS  PubMed  Google Scholar 

  132. Mehedint MG, Zeisel SH. Choline’s role in maintaining liver function: new evidence for epigenetic mechanisms. Curr Opin Clin Nutr Metab Care. 2013;16(3):339–45.

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Spencer MD et al. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology. 2011;140(3):976–86.

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Nan YM et al. Antioxidants vitamin E and 1-aminobenzotriazole prevent experimental non-alcoholic steatohepatitis in mice. Scand J Gastroenterol. 2009;44(9):1121–31.

    CAS  PubMed  Google Scholar 

  135. Landrier JF et al. Adiponectin expression is induced by vitamin E via a peroxisome proliferator-activated receptor gamma-dependent mechanism. Endocrinology. 2009;150(12):5318–25.

    CAS  PubMed  Google Scholar 

  136. Musso G et al. Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology. 2005;42(5):1175–83.

    CAS  PubMed  Google Scholar 

  137. Kang JS et al. A combination of grape extract, green tea extract and L-carnitine improves high-fat diet-induced obesity, hyperlipidemia and non-alcoholic fatty liver disease in mice. Phytother Res. 2011;25(12):1789–95.

    CAS  PubMed  Google Scholar 

  138. Marcolin E et al. Quercetin treatment ameliorates inflammation and fibrosis in mice with nonalcoholic steatohepatitis. J Nutr. 2012;142(10):1821–8.

    CAS  PubMed  Google Scholar 

  139. Bose M et al. The major green tea polyphenol, (-)-epigallocatechin-3-gallate, inhibits obesity, metabolic syndrome, and fatty liver disease in high-fat-fed mice. J Nutr. 2008;138(9):1677–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Zhang W et al. Betaine protects against high-fat-diet-induced liver injury by inhibition of high-mobility group box 1 and Toll-like receptor 4 expression in rats. Dig Dis Sci. 2013;58(11):3198–206.

    CAS  PubMed  Google Scholar 

  141. Wang L et al. Betaine supplement alleviates hepatic triglyceride accumulation of apolipoprotein E deficient mice via reducing methylation of peroxisomal proliferator-activated receptor alpha promoter. Lipids Health Dis. 2013;12:34.

    PubMed Central  PubMed  Google Scholar 

  142. Wang LJ et al. Betaine attenuates hepatic steatosis by reducing methylation of the MTTP promoter and elevating genomic methylation in mice fed a high-fat diet. J Nutr Biochem. 2014;25(3):329–36.

    PubMed  Google Scholar 

  143. Ganji SH et al. Therapeutic role of niacin in the prevention and regression of hepatic steatosis in rat model of nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol. 2014;306(4):G320–7.

    CAS  PubMed  Google Scholar 

  144. Roth CL 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.

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are supported by National Strategic reference Framework (NSRF) 2007-2013 Programme for Development - Quality of Life for Everyone; the European Regional Development Fund (ERDF) 2007-2013; and the OPCE II: Operational Programme “Competitiveness and Entrepreneurship,” Hellenic Ministry of Development and Competitiveness (Grant No: 09-ΣΥΝ-12-890).

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Conflict of Interest

Ioanna-Panagiota Kalafati, Dimitra Borsa, and George V.Z. Dedoussis declare that they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. Department of Dietetics-Nutrition, Harokopio University, 70 El Venizelou Avenue, 17671, Athens, Greece

    Ioanna-Panagiota Kalafati, Dimitra Borsa & George V. Z. Dedoussis

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  1. Ioanna-Panagiota Kalafati
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  2. Dimitra Borsa
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Kalafati, IP., Borsa, D. & Dedoussis, G.V.Z. The Genetics of Nonalcoholic Fatty Liver Disease: Role of Diet as a Modifying Factor. Curr Nutr Rep 3, 223–232 (2014). https://doi.org/10.1007/s13668-014-0085-3

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