nogrЭкспериментальная и клиническая гастроэнтерологияExperimental and Clinical Gastroenterology1682-8658«Global Media Technologies»10.31146/1682-8658-ecg-203-7-171-176nogr-2026Research ArticleОБЗОРREVIEWНеалкогольная жировая болезнь печени: эпигенетический взгляд на патогенез и новые возможности терапииNon-alcoholic fatty liver disease: an epigenetic view of pathogenesis and a new treatment optionshttps://orcid.org/0000-0003-4973-039XАйтбаевКубаныч АвеновичAitbaevKubanich A.noemail@neicon.ruhttps://orcid.org/0000-0001-8513-9279МуркамиловИлхом ТоробековичMurkamilovIlkhom T.murkamilov.i@mail.ruhttps://orcid.org/0000-0002-7653-0433МуркамиловаЖамила АбдилалимовнаMurkamilovaZhamila A.noemail@neicon.ruhttps://orcid.org/0000-0002-2682-4417ФоминВиктор ВикторовичFominViktor V.noemail@neicon.ruhttps://orcid.org/0000-0003-3007-8127КудайбергеноваИндира ОрозобаевнаKudaibergenovaIndira O.noemail@neicon.ruЮсуповФуркат АбдулахатовичYusupovFurkat A.noemail@neicon.ruНаучно-исследовательский институт молекулярной биологии и медициныРоссияScientific Research Institute of Molecular Biology and MedicineRussian FederationКыргызская государственная медицинская академия им. И. К. Ахунбаева; Кыргызско-Российский Славянский университет им. первого Президента России Б. Н. ЕльцинаРоссияKyrgyz State Medical Academy named after I. K. Akhunbaye; Kyrgyz Russian Slavic University named after the First President of Russia B. N. YeltsinRussian FederationКыргызско-Российский Славянский университет им. первого Президента России Б. Н. ЕльцинаРоссияKyrgyz Russian Slavic University named after the First President of Russia B. N. YeltsinRussian FederationФГАОУ ВО Первый Московский государственный медицинский университет им. И. М. Сеченова (Сеченовский Университет)РоссияFSAEI HE First Moscow State Medical University named after I. M. SechenovRussian FederationКыргызская государственная медицинская академия им. И. К. АхунбаеваРоссияKyrgyz State Medical Academy named after I. K. AkhunbayeRussian FederationОшский государственный университетРоссияOsh State UniversityRussian Federation20220710202207171176Copyright © Айтбаев К.А., Муркамилов И.Т., Муркамилова Ж.А., Фомин В.В., Кудайбергенова И.О., Юсупов Ф.А., 20222022Айтбаев К.А., Муркамилов И.Т., Муркамилова Ж.А., Фомин В.В., Кудайбергенова И.О., Юсупов Ф.А.Aitbaev K.A., Murkamilov I.T., Murkamilova Z.A., Fomin V.V., Kudaibergenova I.O., Yusupov F.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.nogr.org/jour/article/view/2026

Неалкогольная жировая болезнь печени (НАЖБП) является наиболее распространенной причиной хронического заболевания печени. НАЖБП вызывает широкий спектр заболеваний печени, начиная от простого стеатоза - до неалкогольного стеатогепатита (НАСГ) и прогрессирующего фиброза печени. Многочисленные исследования показывают, что эпигенетические процессы участвуют и в патогенезе НАЖБП. Сдвиги в регулярности метилирования геномной ДНК могут вызывать аберрантную экспрессию гена при НАЖБП. Патогенез НАЖБП не совсем понятен, но хорошо известно, что ожирение, диабет и метаболические нарушения играют значительную роль в развитии и прогрессировании заболевания. Эпигенетика, известная как наследственное явление, которое влияет на экспрессию гена без изменения последовательности ДНК, предлагает новый взгляд на патогенез НАЖБП. Более того, эпигенетические механизмы, включая метилирование ДНК, посттрансляционные гистоновые модификации и некодирующие РНК, по-видимому, управляют различными аспектами НАЖБП. Ацетилирование гистонов влияет на профили экспрессии генов при НАЖБП. Аномальные изменения гистонов индуцируют резитентность к инсулину, прогрессирование сахарного диабета 2-го типа, и развитие в последующем НАЖБП. Настоящий обзор отражает новые достижения в изучении эпигенетических механизмов развития НАЖБП и формирования на их основе инновационных терапевтических мишеней и долгожданных диагностических и прогностических средств.

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.

неалкогольная жировая болезнь печени (НАЖБП)эпигенетикаметилирование ДНКпеченьстеатозмодификации гистоновнекодирующие РНКnonalcoholic fatty liver disease (NAFLD)epigeneticsDNA methylationliversteatosishistone modificationsnon-coding RNAsReferencesAngulo P. Non-alcoholic fatty liver disease. N Engl J Med. 2002;346:1221-1231. doi: 10.1056/NEJMra011775Angulo P. Non-alcoholic fatty liver disease. N Engl J Med. 2002;346:1221-1231. doi: 10.1056/NEJMra011775Adams 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.2005.04.014Adams 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.2005.04.014Williams 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.2010.09.038Williams 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.2010.09.038Ajmera 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.29055Ajmera 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.29055Ruhl 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.13012Ruhl 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.13012Le 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.0173499Le 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.0173499Ivashkin 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: 10.22416/1382-4376-2016-26-2-24-42Ivashkin 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: 10.22416/1382-4376-2016-26-2-24-42Sookoian 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.23927Sookoian 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.23927Lee 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/nu6083303Lee 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/nu6083303Regele 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/gfv087Regele 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/gfv087Portela A., Esteller M. Epigenetic modifications and human disease. Nature Biotechnology. 2010; 28 (10):1057-1068. doi: 10.1038/nbt.1685Portela A., Esteller M. Epigenetic modifications and human disease. Nature Biotechnology. 2010; 28 (10):1057-1068. doi: 10.1038/nbt.1685Thomas M. C. Epigenetic mechanisms in diabetic kidney disease. Current Diabetes Reports. 2016.16.31. doi: 10.1007/s11892-016-0723-9Thomas M. C. Epigenetic mechanisms in diabetic kidney disease. Current Diabetes Reports. 2016.16.31. doi: 10.1007/s11892-016-0723-9Slomko H., Heo H. J., Einstein F. H. Minireview: Epigenetics of obesity and diabetes in humans. Endocrinology. 2012;153:1025-1030. doi:10.1210/en.2011-1759Slomko H., Heo H. J., Einstein F. H. Minireview: Epigenetics of obesity and diabetes in humans. Endocrinology. 2012;153:1025-1030. doi:10.1210/en.2011-1759Zimmer 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.2011.02.007Zimmer 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.2011.02.007de 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.19774de 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.19774Mehra M., Chauhan R. Long non-coding RNAs as a key player in hepatocellular carcinoma. Biomark Cancer. 2017;9:1179299X17737301Mehra M., Chauhan R. Long non-coding RNAs as a key player in hepatocellular carcinoma. Biomark Cancer. 2017;9:1179299X17737301Vickers MH. Early life nutrition, epigenetics and programming of later life disease. Nutrients. 2014;6:2165-2178. doi: 10.3390/nu6062165Vickers MH. Early life nutrition, epigenetics and programming of later life disease. Nutrients. 2014;6:2165-2178. doi: 10.3390/nu6062165Yokoyama 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.15528Yokoyama 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.15528Eslam 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.2017.09.003Eslam 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.2017.09.003Wilson 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.2017.10.011Wilson 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.2017.10.011Lyall 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: 10.1080/15592294.2019.1649527Lyall 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: 10.1080/15592294.2019.1649527Gibbs 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.1000952Gibbs 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.1000952Ding 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.0190299Ding 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.0190299Maschietto 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.14208Maschietto 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.14208Portela 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.2013.162Portela 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.2013.162Jones P. A. Functions of DNA methylation: islands, startsites, gene bodies and beyond. Nature Reviews Genetics. 2012;13(7):484-492. doi: 10.1038/nrg3230Jones P. A. Functions of DNA methylation: islands, startsites, gene bodies and beyond. Nature Reviews Genetics. 2012;13(7):484-492. doi: 10.1038/nrg3230Pendina 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):27-37Pendina 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):27-37Pirola 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-2012-302962Pirola 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-2012-302962Klose 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.2005.12.008Klose 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.2005.12.008Pogribny 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.2009.03.021Pogribny 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.2009.03.021Murphy 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.2013.07.047Murphy 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.2013.07.047Gerhard 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/s13148-018-0525-9Gerhard 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/s13148-018-0525-9Zeybel 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/s13148-015-0056-6Zeybel 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/s13148-015-0056-6Chen 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.11.16.2124Chen 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.11.16.2124Hardy T., Mann D. A. Epigenetics in liver disease: From biology to therapeutics. Gut. 2016; 65: 1895-1905. doi: 10.1136/gutjnl-2015-311292Hardy T., Mann D. A. Epigenetics in liver disease: From biology to therapeutics. Gut. 2016; 65: 1895-1905. doi: 10.1136/gutjnl-2015-311292Xie 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.113.002416Xie 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.113.002416Tian 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.2013.08.010Tian 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.2013.08.010Ling C., Groop L. Epigenetics: A molecular link between environmental factors and type 2 diabetes. Diabetes. 2009;58:2718-2725. doi:10.2337/db09-1003Ling C., Groop L. Epigenetics: A molecular link between environmental factors and type 2 diabetes. Diabetes. 2009;58:2718-2725. doi:10.2337/db09-1003Chan H.M., La Thangue N. B. p300/CBP proteins: HATs for transcriptional bridges and scaffolds. J Cell Sci.2001;114:2363-2373Chan H.M., La Thangue N. B. p300/CBP proteins: HATs for transcriptional bridges and scaffolds. J Cell Sci.2001;114:2363-2373Bricambert 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/JCI41624Bricambert 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/JCI41624Gallego-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.i24.2497Gallego-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.i24.2497Feng 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.1198125Feng 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.1198125He 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.2012.07.023He 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.2012.07.023Kozomara 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/gkt1181Kozomara 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/gkt1181Gao L., Jiang F. MicroRNA (miRNA) Profiling. Methods Mol Biol. 2016;1381:151-161. doi: 10.1007/978-1-4939-3204-7_8Gao L., Jiang F. MicroRNA (miRNA) Profiling. Methods Mol Biol. 2016;1381:151-161. doi: 10.1007/978-1-4939-3204-7_8Awazawa 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.4420Awazawa 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.4420Pirola 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-2014-306996Pirola 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-2014-306996Fan 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.M115.050344Fan 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.M115.050344Kong 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/s00592-010-0226-0Kong 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/s00592-010-0226-0Dattaroy 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.00346.2014Dattaroy 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.00346.2014Ogawa 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-2011-300717Ogawa 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-2011-300717Callegari 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.25747Callegari 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

The authors declare that there are no conflicts of interest present.