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Non-alcoholic fatty liver disease: an epigenetic view of pathogenesis and a new treatment options

https://doi.org/10.31146/1682-8658-ecg-203-7-171-176

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common reason of chronic liver disease. NAFLD causes a wide array of liver conditions ranging from simple steatosis - to nonalcoholic steatohepatitis (NASH) and advanced hepatic fibrosis. Numerous studies show that epigenetic processes are also involved in the pathogenesis of NAFLD. Shifts in the regularity of genomic DNA methylation can cause aberrant gene expression in NAFLD. Pathogenesis of NAFLD is not entirely understood, but it is well-known that obesity, diabetes and metabolic abnormalities played a significant role in the disease development and progression. Epigenetics is known as an inheritable phenomenon which influences the expression of gene without altering the DNA sequence, offers a new view on the pathogenesis of NAFLD. Moreover, epigenetic mechanisms including DNA methylation, posttranslational histone modifications and non-coding RNAs seem to orchestrate various aspects of NAFLD. Histone acetylation affects gene expression profiles in NAFLD. Abnormal histone changes induce insulin resistance, progression of type 2 diabetes mellitus, and subsequent development of NAFLD. This review reflects new advances in the study of epigenetic mechanisms for the development of NAFLD and the formation of innovative therapeutic targets and the long-awaited diagnostic and prognostic tools based on them.

About the Authors

Kubanich A. Aitbaev
Scientific Research Institute of Molecular Biology and Medicine
Russian Federation


Ilkhom T. Murkamilov
Kyrgyz State Medical Academy named after I. K. Akhunbaye; Kyrgyz Russian Slavic University named after the First President of Russia B. N. Yeltsin
Russian Federation


Zhamila A. Murkamilova
Kyrgyz Russian Slavic University named after the First President of Russia B. N. Yeltsin
Russian Federation


Viktor V. Fomin
FSAEI HE First Moscow State Medical University named after I. M. Sechenov
Russian Federation


Indira O. Kudaibergenova
Kyrgyz State Medical Academy named after I. K. Akhunbaye
Russian Federation


Furkat A. Yusupov
Osh State University
Russian Federation


References

1. Angulo P. Non-alcoholic fatty liver disease. N Engl J Med. 2002;346:1221-1231. doi: 10.1056/NEJMra011775

2. Adams L.A., Lymp J. F., St Sauver J., Sanderson S. O., Lindor K. D., Feldstein A., Angulo P. The natural history of nonalcoholic fatty liver disease: A population based cohort study. Gastroenterology. 2005;129:113-121. doi: 10.1053/j.gastro.2005.04.014

3. Williams C.D., Stengel J., Asike M. I., Torres D. M., Shaw J., Contreras M., Harrison S. A. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: A prospective study. Gastroenterology. 2011;140:124-131. doi: 10.1053/j.gastro.2010.09.038

4. Ajmera V.H., Terrault N. A., Harrison S. A. Is moderate alcohol use in nonalcoholic fatty liver disease good or bad? A critical review. Hepatology. 2017;65:2090-2099. doi: 10.1002/hep.29055

5. Ruhl C.E., Everhart J. E. Fatty liver indices in the multiethnic United States National Health and Nutrition Examination Survey. Aliment Pharmacol Ther. 2005;41:65-76. doi: 10.1111/apt.13012

6. Le M.H., Devaki P., Ha N. B., Jun D. W., Te H. S., Cheung R. C., Nguyen M. H. Prevalence of non-alcoholic fatty liver disease and risk factors for advanced fibrosis and mortality in the United States. PLoS One. 2017;12: e0173499. doi: 10.1371/journal.pone.0173499

7. Ivashkin V. T., Mayevskaya M. V., Pavlov C. S., et al. Diagnostics and treatment of non-alcoholic fatty liver disease: clinical guidelines of the Russian Scientific Liver Society and the Russian gastroenterological association.Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2016;26(2):24-42. (In Russ.) doi: 10.22416/1382-4376-2016-26-2-24-42 @@Ивашкин В. Т., Маевская М. В., Павлов Ч. С., Тихонов И. Н., Широкова Е. Н., Буеверов А. О., Драпкина О. М., Шульпекова Ю. О., Цуканов В. В., Маммаев С. Н., Маев И. В., Пальгова Л. К. Клинические рекомендации по диагностике и лечению неалкогольной жировой болезни печени Российского общества по изучению печени и Российской гастроэнтерологической ассоциации. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2016;26(2):24-42. doi: 10.22416/1382-4376-2016-26-2-24-42

8. Sookoian S., Rosselli M. S., Gemma C., Burgueño A. L., Fernández Gianotti T., Castaño G. O., Pirola C. J. 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;52:1992-2000. doi: 10.1002/hep.23927

9. Lee J.H., Friso S., Choi S. W. Epigenetic mechanisms underlying the link between non-alcoholic fatty liver diseases and nutrition. Nutrients. 2014;6:3303-3325. doi: 10.3390/nu6083303

10. Regele F., Jelencsics K., Shiffman D., Paré G., McQueen M.J., Mann J. F., Oberbauer R. Genome-wide studies to identify risk factors for kidney disease with a focus on patients with diabetes. Nephrology Dialysis Transplantation. 2015;30(4): iv26-iv34. doi: 10.1093/ndt/gfv087

11. Portela A., Esteller M. Epigenetic modifications and human disease. Nature Biotechnology. 2010; 28 (10):1057-1068. doi: 10.1038/nbt.1685

12. Thomas M. C. Epigenetic mechanisms in diabetic kidney disease. Current Diabetes Reports. 2016.16.31. doi: 10.1007/s11892-016-0723-9

13. Slomko H., Heo H. J., Einstein F. H. Minireview: Epigenetics of obesity and diabetes in humans. Endocrinology. 2012;153:1025-1030. doi:10.1210/en.2011-1759

14. Zimmer V., Lammert F. Genetics and epigenetics in the fibrogenic evolution of chronic liver diseases. Best Pract Res Clin Gastroenterol. 2011;25:269-280. doi: 10.1016/j.bpg.2011.02.007

15. de Conti A., Ortega J. F., Tryndyak V., Dreval K., Moreno F. S., Rusyn I., Pogribny I. P. MicroRNA deregulation in nonalcoholic steatohepatitis-associated liver carcinogenesis. Oncotarget. 2017;8:88517-88528. doi: 10.18632/oncotarget.19774

16. Mehra M., Chauhan R. Long non-coding RNAs as a key player in hepatocellular carcinoma. Biomark Cancer. 2017;9:1179299X17737301

17. Vickers MH. Early life nutrition, epigenetics and programming of later life disease. Nutrients. 2014;6:2165-2178. doi: 10.3390/nu6062165

18. Yokoyama M., Chiba T., Zen Y., Oshima M., Kusakabe Y., Noguchi Y., Iwama A. Histone lysine methyltransferase G9a is a novel epigenetic target for the treatment of hepatocellular carcinoma. Oncotarget. 2017;8:21315-21326. doi: 10.18632/oncotarget.15528

19. Eslam M., Valenti L., Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact. Journal of hepatology. 2018;68:2:268-279. doi: 10.1016/j.jhep.2017.09.003

20. Wilson C.L., Mann D. A., Borthwick L. A. Epigenetic reprogramming in liver fibrosis and cancer. Adv Drug Deliv Rev. 2017;121: 124-132. doi: 10.1016/j.addr.2017.10.011

21. Lyall M.J., Thomson J. P., Cartier J., Ottaviano R., Kendall T. J., Meehan R. R., Drake A. J. Non-alcoholic fatty liver disease (NAFLD) is associated with dynamic changes in hydroxymethylation. Epigenetics. 2020;15(1-2):61-71. doi: 10.1080/15592294.2019.1649527

22. Gibbs J.R., van der Brug M. P., Hernandez D. G., Traynor B. J., Nalls M. A., Lai S. L., Singleton A. B. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet. 2010;6: e1000952. doi: 10.1371/journal.pgen.1000952

23. Ding C.J., Liang L. X., Diao S., Su X. H., Zhang B. Y. Genome-wide analysis of day/night DNA methylation differences in Populus nigra. PLoS One. 2018;13: e0190299. doi: 10.1371/journal.pone.0190299

24. Maschietto M., Rodrigues T. C., Kashiwabara A. Y., Setién F., Villanueva A., Esteller M. DNA methylation landscape of hepatoblastomas reveals arrest at early stages of liver differentiation and cancer-related alterations. Oncotarget. 2016;8:97871-97889. doi: 10.18632/oncotarget.14208

25. Portela A., Liz J., Nogales V., Setién F., Villanueva A., Esteller M. DNA methylation determines nucleosome occupancy in the 5’-CpG islands of tumor suppressor genes. Oncogene. 2013;32:5421-5428. doi: 10.1038/onc.2013.162

26. Jones P. A. Functions of DNA methylation: islands, startsites, gene bodies and beyond. Nature Reviews Genetics. 2012;13(7):484-492. doi: 10.1038/nrg3230

27. Pendina A. A., Grinkevich V. V., Kuznetsova T. V., Baranov V. S. Metilirovanie DNK - universal’nyi mekhanizm regulyatsii aktivnosti genov. [DNA methylation is a universal mechanism for regulating gene activity]. Ecological genetics. 2004; 1(II): 27-37 (In Russ.) @@Пендина А. А., Гринкевич В. В., Кузнецова Т. В., Баранов В. С. Метилирование ДНК - универсальный механизм регуляции активности генов. Экологическая генетика 2004; II (1):27-37

28. Pirola C.J., Gianotti T. F., Burgueño A. L., Rey-Funes M., Loidl C. F., Mallardi P., Sookoian, S. Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut. 2006;62: 1356-1363. doi: 10.1136/gutjnl-2012-302962

29. Klose R.J., Bird A. P. Genomic DNA methylation: The mark and its mediators. Trends Biochem Sci. 2006;31:89-97. doi: 10.1016/j.tibs.2005.12.008

30. Pogribny I.P., Tryndyak V. P., Bagnyukova T. V., Bagnyukova T. V., Melnyk S., Montgomery B., Ross S. A., Beland F. A. Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyldeficient diet. J Hepatol. 2009;51:176-186. doi: 10.1016/j.jhep.2009.03.021

31. Murphy S.K., Yang H., Moylan C. A., Moylan C. A., Pang H., Dellinger A., Abdelmalek M. F., Diehl A. M. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology. 2013;145:1076-1087. doi: 10.1053/j.gastro.2013.07.047

32. Gerhard G.S., Malenica I., Llaci L., Chu X., Petrick A. T., Still C. D., DiStefano J. K. Differentially methylated loci in NAFLD cirrhosis are associated with key signaling pathways. Clinical Epigenetics. 2018;10:93. doi: 10.1186/s13148-018-0525-9

33. Zeybel M., Hardy T., Robinson S. M., Fox C., Anstee Q. M., Ness T., Masson S. Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease. Clin Epigenetics. 2015;7:25. doi: 10.1186/s13148-015-0056-6

34. Chen Z.J., Pikaard C. S. 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

35. Hardy T., Mann D. A. Epigenetics in liver disease: From biology to therapeutics. Gut. 2016; 65: 1895-1905. doi: 10.1136/gutjnl-2015-311292

36. Xie M., Kong Y., Tan W., May H., Battiprolu P. K., Pedrozo Z., Hill J. A. Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation. 2014;129:1139-1151. doi: 10.1161/CIRCULATIONAHA.113.002416

37. Tian Y., Wong V. W., Chan H. L., Cheng A. S. Epigenetic regulation of hepatocellular carcinoma in non-alcoholic fatty liver disease. Semin Cancer Biol. 2013;23:471-482. doi: 10.1016/j.semcancer.2013.08.010

38. Ling C., Groop L. Epigenetics: A molecular link between environmental factors and type 2 diabetes. Diabetes. 2009;58:2718-2725. doi:10.2337/db09-1003

39. Chan H.M., La Thangue N. B. p300/CBP proteins: HATs for transcriptional bridges and scaffolds. J Cell Sci.2001;114:2363-2373

40. 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;120:4316-4331. doi: 10.1172/JCI41624

41. Gallego-Durán R., Romero-Gómez M. Epigenetic mechanisms in non-alcoholic fatty liver disease: An emerging field. World J Hepatol. 2015;7:2497-2502. doi: 10.4254/wjh.v7.i24.2497

42. Feng D., Liu T., Sun Z., Pop E. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science. 2011;331:1315-1319. doi: 10.1126/science.1198125

43. He Y., Huang C., Zhang S. P., Sun X., Long X. R., Li J. The potential of microRNAs in liver fibrosis. Cell Signal. 2012;24:2268-2272. doi: 10.1016/j.cellsig.2012.07.023

44. Kozomara A., Griffiths-Jones S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Research. 2014;42(1): D68-D73. doi: 10.1093/nar/gkt1181

45. Gao L., Jiang F. MicroRNA (miRNA) Profiling. Methods Mol Biol. 2016;1381:151-161. doi: 10.1007/978-1-4939-3204-7_8

46. Awazawa M., Gabel P., Tsaousidou E., Nolte H., Krüger M., Schmitz J., Brüning J. C.A microRNA screen reveals that elevated hepatic ectodysplasin A expression contributes to obesity-induced insulin resistance in skeletal muscle. Nat Med. 2017;23:1466-1473. doi: 10.1038/nm.4420

47. Pirola C.J., Fernández Gianotti T., Castaño G. O., Mallardi P., San Martino J., Ledesma M. M.G. L., Sookoian S. Circulating microRNA signature in non-alcoholic fatty liver disease: From serum non-coding RNAs to liver histology and disease pathogenesis. Gut. 2015;64:800-812. doi: 10.1136/gutjnl-2014-306996

48. Fan B., Sutandy F. X., Syu G. D., Middleton., S., Yi G., Lu K. Y., Kao C. C. Heterogeneous Ribonucleoprotein K (hnRNP K) Binds miR-122, a Mature Liver-Specific MicroRNA Required for Hepatitis C Virus Replication. Mol Cell Proteomics. 2015;14:2878-2886. doi: 10.1074/mcp.M115.050344

49. Kong L., Zhu J., Han W., Jiang X., Xu M., Zhao Y., Zhao L. Significance of serum microRNAs in pre-diabetes and newly diagnosed type 2 diabetes: a clinical study. Acta Diabetol. 2011;48:61-69. doi: 10.1007/s00592-010-0226-0

50. Dattaroy D., Pourhoseini S., Das S., Alhasson F., Seth R. K., Nagarkatti M., Chatterjee S. Micro-RNA 21 inhibition of SMAD7 enhances fibrogenesis via leptinmediated NADPH oxidase in experimental and human nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 2015;308: G298-G312. doi: 10.1152/ajpgi.00346.2014

51. Ogawa T., Enomoto M., Fujii H., Sekiya Y., Yoshizato K., Ikeda K., Kawada N. MicroRNA-221/222 upregulation indicates the activation of stellate cells and the progression of liver fibrosis. Gut. 2012;61:1600-1609. doi: 10.1136/gutjnl-2011-300717

52. Callegari E., Elamin B. K., Giannone F., Milazzo M., Altavilla G., Fornari F., Negrini M. Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model. Hepatology. 2012;56:1025-1033. doi: 10.1002/hep.25747


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For citations:


Aitbaev K.A., Murkamilov I.T., Murkamilova Zh.A., Fomin V.V., Kudaibergenova I.O., Yusupov F.A. Non-alcoholic fatty liver disease: an epigenetic view of pathogenesis and a new treatment options. Experimental and Clinical Gastroenterology. 2022;(7):171-176. (In Russ.) https://doi.org/10.31146/1682-8658-ecg-203-7-171-176

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