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2017, Number 4

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Ann Hepatol 2017; 16 (4)

Genetic and Epigenetic Profile of Patients With Alcoholic Liver Disease

Boccuto L, Abenavoli L

Language: English
References: 78
Page: 490-500
PDF size: 214.27 Kb.


ABSTRACT

Alcoholic liver disease (ALD) is a definition encompassing a spectrum of disorders ranging from simple steatosis to cirrhosis and hepatocellular carcinoma. Excessive alcohol consumption triggers a series of metabolic reactions that affect the liver by inducing lipogenesis, increasing oxidative stress, and causing abnormal inflammatory responses. The metabolic pathways regulating lipids, reactive oxygen species (ROS), and immune system are closely related and in some cases cross-regulate each other. Therefore, it must be taken into account that major genetic and epigenetic abnormalities affecting enzymes involved in one of such pathways can play a pivotal role in ALD pathogenesis. However, recent studies have pointed out how a significant predisposition can also be determined by minor variants, such as relatively common polymorphisms, epigenetic modifications, and microRNA abnormalities. Genetic and epigenetic factors can also affect the progression of liver diseases, promoting fibrogenesis, cirrhosis, and ultimately hepatocellular carcinoma. It is noteworthy that some of these factors, such as some of the cytokines involved in the abnormal inflammatory responses, are shared with non-alcoholic liver disease, while other factors are unique to ALD. The study of the genetic and epigenetic components involved in the liver damages caused by alcohol is crucial to identify individuals with high risk of developing ALD, design personalized protocols for prevention and/or treatment, and select the best molecular targets for new therapies.


REFERENCES

  1. Masarone M, Rosato V, Dallio M, Abenavoli L, Federico A, Loguercio C, Persico M. Epidemiology and natural history of alcoholic liver disease. Rev Recent Clin Trials 2016; 11: 167-74.

  2. Roerecke M, Nanau R, Rehm J, Neuman M. Ethnicity matters: A Systematic Review and Meta-Analysis of the Non-Linear Relationship Between Alcohol Consumption and Prevalence and Incidence of Hepatic Steatosis. EBioMedicine 2016; 8: 317-30.

  3. Abenavoli L, Masarone M, Federico A, Rosato V, Dallio M, Loguercio C, Persico M. Alcoholic hepatitis: pathogenesis, diagnosis and treatment. Rev Recent Clin Trials 2016; 11: 159-66.

  4. Mathurin P, Bataller R. Trends in the management and burden of alcoholic liver disease. J Hepatol 2015; 62: S38-46.

  5. Bellentani S, Saccoccio G, Costa G, Tiribelli C, Manenti F, Sodde M, Crocè L, et al. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group. Gut 1997; 41: 845-50.

  6. European Association for the Study of Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol 2012; 57: 399-420.

  7. Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. J Hepatol 2013; 59: 160-8.

  8. Dwyer-Lindgren L, Flaxman AD, Ng M, Hansen GM, Murray CJ, Mokdad AH. Drinking patterns in US Countries from 2002 to 2012. Am J Public Health 2015; 105: 1120-7.

  9. Flores YN, Yee HF Jr, Leng M, Escarce JJ, Bastani R, Salmerón J, Morales LS. Risk factors for chronic liver disease in Blacks, Mexican Americans, and Whites in the United States: results from NHANES IV, 1999-2004. Am J Gastroenterol 2008; 103; 2231-8.

  10. Stokkeland K, Hilm G, Spak F, Franck J, Hultcrantz R. Different drinking patterns for women and men with alcohol dependence with and without alcoholic cirrhosis. Alcohol Alcohol 2008; 43: 39-45.

  11. Stickel F, Hampe J. Genetic determinants of alcoholic liver disease. Gut 2012; 61: 150-9.

  12. Stickel F, Moreno C, Hampe J, Morgan MY. The genetics of alcohol dependence and alcohol-related liver disease. J Hepatol 2017; 66: 195-211.

  13. Anstee QM, Seth D, Day CP. Genetic Factors That Affect Risk of Alcoholic and Nonalcoholic Fatty Liver Disease. Gastroenterology 2016; 150: 1728-44.

  14. Goedde HW, Agarwal DP, Fritze G, Meier-Tackmann D, Singh S, Beckmann G, et al. Distribution of ADH2 and ALDH2 genotypes in different populations. Hum Genet 1992; 88: 344-6.

  15. Eng MY, Luczak SE, Wall TL. ALDH2, ADH1B, and ADH1C genotypes in Asians: a literature review. Alcohol Res Health 2007; 30: 22-7.

  16. Hurley TD, Edenberg HJ. Genes encoding enzymes involved in ethanol metabolism. Alcohol Res 2012; 34: 339-44.

  17. Stickel F, Moreno C, Hampe J, Morgan MY. The genetics of alcohol dependence and alcohol-related liver disease. J Hepatol 2017; 66: 195-211.

  18. Long JC, Knowler WC, Hanson RL, Robin RW, Urbanek M, Moore E, et al. Evidence for genetic linkage to alcohol dependence on chromosomes 4 and 11 from an autosomewide scan in an American Indian population. Am J Med Genet 1998; 81: 216-21.

  19. Treutlein J, Cichon S, Ridinger M, Wodarz N, Soyka M, Zill P, Maier W, et al. Genomewide association study of alcohol dependence. Arch Gen Psychiatry; 2009; 66: 773-84.

  20. Gelernter J, Kranzler HR, Sherva R, Almasy L, Koesterer R, Smith AH, Anton R, et al. Genome-wide association study of alcohol dependence: significant findings in African-and European-Americans including novel risk loci. Mol Psychiatry 2014; 19: 41-9.

  21. Tian C, Stokowski RP, Kershenobich D, Ballinger DG, Hinds DA. Variant in PNPLA3 is associated with alcoholic liver disease. Nat Genet 2010; 42: 21-3.

  22. Dongiovanni P, Donati B, Fares R, Lombardi R, Mancina RM, Romeo S, Valenti L. PNPLA3 I148M polymorphism and progressive liver disease. World J Gastroenterol 2013; 19: 6969-78.

  23. Valenti L, Motta BM, Soardo G, Iavarone M, Donati B, Sangiovanni A, Carnelutti A, et al. PNPLA3 I148M polymorphism, clinical presentation, and survival in patients with hepatocellular carcinoma. PloS One 2013; 8: e75982.

  24. Trepo E, Gustot T, Degre D, Lemmers A, Verset L, Demetter P, Ouziel R, et al. Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease. J Hepatol 2011; 55: 906-12.

  25. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40: 1461-5.

  26. Yuan X, Waterworth D, Perry JR, Lim N, Song K, Chambers JC, Zhang W, et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am J Hum Genet 2008; 83: 520-8.

  27. He S, McPhaul C, Li JZ, Garuti R, Kinch L, Grishin NV, Cohen JC, et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem 2010; 285: 6706-15.

  28. Huang Y, He S, Li JZ, Seo YK, Osborne TF, Cohen JC, Hobbs HH. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci USA 2010; 107: 7892-7.

  29. Pirazzi C, Adiels M, Burza MA, Mancina RM, Levin M, Ståhlman M, Taskinen MR, et al. Patatin-like phospholipase domain- containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J Hepatol 2012; 57: 1276-82.

  30. Kumari M, Schoiswohl G, Chitraju C, Paar M, Cornaciu I, Rangrez AY, Wongsiriroj N, et al. Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab 2012; 15: 691-702.

  31. Basantani MK, Sitnick MT, Cai L, Brenner DS, Gardner NP, Li JZ, Schoiswohl G, et al. Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. J Lipid Res 2011; 52: 318-29.

  32. Li JZ, Huang Y, Karaman R, Ivanova PT, Brown HA, Roddy T, Castro-Perez J, et al. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest 2012; 122: 4130-44.

  33. Kumashiro N, Yoshimura T, Cantley JL, Majumdar SK, Guebre- Egziabher F, Kursawer R, Vatner DF, et al. Role of patatin- like phospholipase domain-containing 3 on lipid-induced hepatic steatosis and insulin resistance in rats. Hepatology 2013; 57: 1763-72.

  34. 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: 1134-42.

  35. Santoro N, Kursawe R, D'Adamo E, Dykas DJ, Zhang CK, Bale AE, Calì AM, 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: 1281-90.

  36. Valenti L, Rametta R, Ruscica M, Dongiovanni P, Steffani L, Motta BM, Canevesi E, et al. The I148M PNPLA3 polymorphism influences serum adiponectin in patients with fatty liver and healthy controls. BMC Gastroenterol 2012; 12: 111.

  37. Ravi Kanth VV, Sasikala M, Sharma M, Rao PN, Reddy DN. Genetics of non-alcoholic fatty liver disease: From susceptibility and nutrient interactions to management. World J Hepatol 2016; 8: 827-37.

  38. Valenti L, Al-Serri A, Daly AK, Galmozzi E, Rametta R, Dongiovanni P, Nobili V, 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: 1209-17.

  39. Valenti L, Rumi M, Galmozzi E, Aghemo A, Del Menico B, De Nicola S, Dongiovanni P, et al. Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. Hepatology 2011; 53: 791-9.

  40. Rembeck K, Maglio C, Lagging M, Christensen PB, Färkkilä M, Langeland N, Buhl MR, et al. PNPLA 3 I148M genetic variant associates with insulin resistance and baseline viral load in HCV genotype 2 but not in genotype 3 infection. BMC Med Genet 2012; 13: 82.

  41. Friedrich K, Rupp C, Hov JR, Steinebrunner N, Weiss KH, Stiehl A, Brune M, et al. A frequent PNPLA3 variant is a sex specific disease modifier in PSC patients with bile duct stenosis. PloS One 2013; 8: e58734.

  42. Fujii H, Kawada N. Fibrogenesis in alcoholic liver disease. World J Gastroenterol 2014; 20: 8048-54.

  43. Wu D, Cederbaum AI. Oxidative stress and alcoholic liver disease. Semin Liver Dis 2009; 29: 141-54.

  44. Shin SM, Yang JH, Ki SH. Role of the Nrf2-ARE pathway in liver diseases. Oxid Med Cell Longev 2013; 2013: 763257.

  45. Tang W, Jiang YF, Ponnusamy M, Diallo M. Role of Nrf2 in chronic liver disease. World J Gastroenterol 2014; 20: 13079-87.

  46. Moi P, Chan K, Asunis I, Cao A, Kan YW. Isolation of NF-E2- related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci USA 1994; 91: 9926-30.

  47. Li W, Kong AN. Molecular mechanisms of Nrf2-mediated antioxidant response. Mol Carcinog 2009; 48: 91-104.

  48. Lu Y, Zhang XH, Cederbaum AI. Ethanol induction of CYP2A5: role of CYP2E1-ROS-Nrf2 pathway. Toxicol Sci 2012; 128: 427-38.

  49. Lamle J, Marhenke S, Borlak J, von Wasielewski R, Eriksson CJ, Geffers R, Manns MP, et al. Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury. Gastroenterology 2008; 134: 1159-6.

  50. Wu KC, Liu J, Klaassen CD. Role of Nrf2 in preventing ethanol- induced oxidative stress and lipid accumulation. Toxicol Appl Pharmacol 2012; 262: 321-9.

  51. Scarpellini E, Forlino M, Lupo M, Rasetti C, Fava G, Abenavoli L, De Santis A. Gut microbiota and alcoholic liver disease. Rev Recent Clin Trials 2016; 11: 213-19.

  52. Bala S, Szabo G. MicroRNA signature in alcoholic liver disease. Int J Hepatol 2012; 2012: 498232.

  53. McDaniel K, Herrera L, Zhou T, Francis H, Han Y, Levine P, Lin E, et al. The functional role of microRNAs in alcoholic liver injury. J Cell Mol Med 2014; 18: 197-2.

  54. Louvet A, Mathurin P. Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol 2015; 12: 231-42.

  55. Baltimore D, Boldin MP, O'Connell RM, Rao DS, Taganov KD. MicroRNAs: new regulators of immune cell development and function. Nat Immunol 2008; 9: 839-45.

  56. Bala S, Marcos M, Kodys K, Csak T, Catalano D, Mandrekar P, Szabo G. Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor {alpha} (TNF{alpha}) production via increased mRNA half-life in alcoholic liver disease. J Biol Chem 2011; 286: 1436-44.

  57. Wang XW, Heegaard NH, Orum H. MicroRNAs in liver disease. Gastroenterology 2012; 142: 1431-3.

  58. Girard M, Jacquemin E, Munnich A, Lyonnet S, Henrion- Caude A. miR-122, a paradigm for the role of microRNAs in the liver. J Hepatol 2008; 8: 648-56.

  59. Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N, Bentwich Z, et al. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell 2007; 26: 731-43.

  60. Lee J, Padhye A, Sharma A, Song G, Miao J, Mo YY, Wang L, 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: 12604-11.

  61. Yin H, Hu M, Liang X, Ajmo JM, Li X, Bataller R, Odena G, et al. Deletion of SIRT1 from hepatocytes in mice disrupts lipin- 1 signaling and aggravates alcoholic fatty liver. Gastroenterology 2014; 146: 801-11.

  62. Harris TE, Finck BN. Dual function lipin proteins and glycerolipid metabolism. Trends Endocrinol Metab 2011; 22: 226- 33.

  63. Peterfy M, Phan J, Xu P, Reue K. Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin. Nat Genet 2001; 27: 121-4.

  64. Yin H, Hu M, Zhang R, Shen Z, Flatow L, You M. MicroRNA- 217 promotes ethanol-induced fat accumulation in hepatocytes by down-regulating SIRT1. J Biol Chem 2012; 287: 9817-26.

  65. Bou Khalil M, Sundaram M, Zhang HY, Links PH, Raven JF, Manmontri B, Sariahmetoglu M, et al. The level and compartmentalization of phosphatidate phosphatase-1 (lipin-1) control the assembly and secretion of hepatic VLDL. J Lipid Res 2009; 50: 47-58.

  66. Pihlajamaki J, Lerin C, Itkonen P, Boes T, Floss T, Schroeder J, Dearie F, et al. Expression of the splicing factor gene SFRS10 is reduced in human obesity and contributes to enhanced lipogenesis. Cell Metab 2011; 14: 208-18.

  67. Zahs A, Curtis BJ, Waldschmidt TJ, Brown LA, Gauthier TW, Choudhry MA, Kovacs EJ, et al. Alcohol and epigenetic changes: summary of the 2011 Alcohol and Immunology Research Interest Group (AIRIG) meeting. Alcohol 2012; 46: 783-7.

  68. Park PH, Lim RW, Shukla SD. Gene-selective histone H3 acetylation in the absence of increase in global histone acetylation in liver of rats chronically fed alcohol. Alcohol Alcohol 2012; 47: 233-9.

  69. Park PH, Lim RW, Shukla SD. Involvement of histone acetyltransferase (HAT) in ethanol-induced acetylation of histone H3 in hepatocytes: potential mechanism for gene expression. Am J Physiol Gastrointest Liver Physiol 2005; 289: G1124-36.

  70. Shukla SD, Lim RW. Epigenetic effects of ethanol on the liver and gastrointestinal system. Alcohol Res 2013; 35: 47-55.

  71. Shukla SD, Restrepo R, Fish P, Lim RW, Ibdah JA. Different mechanisms for histone acetylation by ethanol and its metabolite acetate in rat primary hepatocytes. J Pharmacol Exp Ther 2015; 354: 18-23.

  72. James TT, Aroor AR, Lim RW, Shukla SD. Histone H3 phosphorylation (Ser10, Ser28) and phosphoacetylation (K9S10) are differentially associated with gene expression in liver of rats treated in vivo with acute ethanol. J Pharmacol Exp Ther 2012; 340: 237-47.

  73. Choudhury M, Pandey RS, Clemens DL, Davis JW, Lim RW, Shukla SD. Knock down of GCN5 histone acetyltransferase by siRNA decreases ethanol-induced histone acetylation and affects differential expression of genes in human hepatoma cells. Alcohol 2011; 45: 311-24.

  74. Nagy LE. The role of innate immunity in alcoholic liver disease. Alcohol Res 2015; 37: 237-50.

  75. Curtis BJ, Zahs A, Kovacs EJ. Epigenetic targets for reversing immune defects caused by alcohol exposure. Alcohol Res 2013; 35: 97-113.

  76. Petrasek J, Csak T, Ganz M, Szabo G. Differences in innate immune signaling between alcoholic and non-alcoholic steatohepatitis. J Gastroenterol Hepatol 2013; Suppl 1: 93-8.

  77. Orman ES, Odena G, Bataller R. Alcoholic liver disease: pathogenesis, management, and novel targets for therapy. J Gastroenterol Hepatol; 2013; Suppl 1: 77-84.

  78. Abenavoli L, Milic N, Rouabhia S, Addolorato G. Pharmacotherapy of acute alcoholic hepatitis in clinical practice. World J Gastroenterol 2014; 7: 2159-67.




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