Research on the function of epigenetic regulation in the inflammation of non-alcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver condition, characterized by a spectrum that progresses from simple hepatic steatosis to nonalcoholic steatohepatitis, which may eventually lead to cirrhosis and hepatocellular carcinoma. The precise pathogenic mechanisms underlying NAFLD and its related metabolic disturbances remain elusive. Epigenetic modifications, which entail stable transcriptional changes without altering the DNA sequence, are increasingly recognized as pivotal. The principal forms of epigenetic modifications include DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs. These alterations participate in the regulation of hepatic lipid metabolism, insulin resistance, mitochondrial injury, oxidative stress response, and release of inflammatory cytokines, all of which are associated with the onset and progression of NAFLD. This review discussed recent advances in understanding the potential epigenetic regulation of inflammation in NAFLD. Unraveling these epigenetic mechanisms may facilitate the identification of early diagnostic biomarkers and the development of targeted therapeutic strategies for NAFLD.

Keywords

epigenetics / nonalcoholic fatty liver disease / inflammation

References

[1] Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol 2012; 56: 1384- 91.

[2] Abd El-Kader SM, El-Den Ashmawy EM. Non-alcoholic fatty liver disease: the diagnosis and management. World J Hepatol 2015; 7: 846- 58.

[3] Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J Hepatol 2018; 68: 268- 79.

[4] Wong VW, Chitturi S, Wong GL, et al. Pathogenesis and novel treatment options for non-alcoholic steatohepatitis. Lancet Gastroenterol Hepatol 2016; 1: 56- 67.

[5] Nacev BA, Jones KB, Intlekofer AM, et al. The epigenomics of sarcoma. Nat Rev Cancer 2020; 20: 608- 23.

[6] Li X, Wang J, Wang L, et al. Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging. Signal Transduct Target Ther 2022; 7: 162.

[7] Centis E, Marzocchi R, Di Domizio S, et al. The effect of lifestyle changes in non-alcoholic fatty liver disease. Dig Dis 2010; 28: 267- 73.

[8] Lean MEJ, Astrup A, Roberts SB. Making progress on the global crisis of obesity and weight management. Br Med J 2018; 361: k2538.

[9] Younossi ZM. Non-alcoholic fatty liver disease—a global public health perspective. J Hepatol 2019; 70: 531- 44.

[10] Ekstedt M, Hagström H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015; 61: 1547- 54.

[11] Le P, Payne JY, Zhang L, et al. Disease state transition probabilities across the spectrum of NAFLD: a systematic review and metaanalysis of paired biopsy or imaging studies. Clin Gastroenterol Hepatol 2023; 21: 1154- 68.

[12] Lebeaupin C, Vallée D, Hazari Y, et al. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol 2018; 69: 927- 47.

[13] Arguello G, Balboa E, Arrese M, et al. Recent insights on the role of cholesterol in non-alcoholic fatty liver disease. Biochim Biophys Acta 2015; 1852: 1765- 78.

[14] Seki E, Schwabe RF. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology 2015; 61: 1066- 79.

[15] Aron-Wisnewsky J, Vigliotti C, Witjes J, et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol 2020; 17: 279- 97.

[16] Chen J, Vitetta L. Letter to the Editor: could butyrate be incorporated with farnesoid X receptor agonist cilofexor to enhance primary sclerosing cholangitis treatment? Hepatology 2020; 72: 1497- 8.

[17] Chen J, Vitetta L. Butyrate in inflammatory bowel disease therapy. Gastroenterology 2020; 158: 1511.

[18] Boursier J, Mueller O, Barret M, et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 2016; 63: 764- 75.

[19] Cai J, Zhang XJ, Li H. Role of innate immune signaling in non-alcoholic fatty liver disease. Trends Endocrinol Metabol 2018; 29: 712- 22.

[20] Sagan L. On the origin of mitosing cells. J Theor Biol 1967; 14: 255- 74.

[21] Eguchi A, Yan R, Pan SQ, et al. Comprehensive characterization of hepatocyte-derived extracellular vesicles identifies direct miRNA-based regulation of hepatic stellate cells and DAMP-based hepatic macrophage IL-1β and IL-17 upregulation in alcoholic hepatitis mice. J Mol Med (Berl) 2020; 98: 1021- 34.

[22] Wang M, Shen G, Xu L, et al. IL-1 receptor like 1 protects against alcoholic liver injury by limiting NF-κB activation in hepatic macrophages. J Hepatol 2017; 68: 109- 17.

[23] Maccioni L, Gao B, Leclercq S, et al. Intestinal permeability, microbial translocation, changes in duodenal and fecal microbiota, and their associations with alcoholic liver disease progression in humans. Gut Microbes 2020; 12: 1782157.

[24] Szabo G. Gut-liver axis in alcoholic liver disease. Gastroenterology 2015; 148: 30- 6.

[25] Seo B, Jeon K, Moon S, et al. Roseburia spp. Abundance associates with alcohol consumption in humans and its administration ameliorates alcoholic fatty liver in mice. Cell Host Microbe 2020; 27: 25- 40.e6.

[26] Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 2011; 141: 1572- 85.

[27] Avila MA, Dufour JF, Gerbes AL, et al. Recent advances in alcoholrelated liver disease (ALD): summary of a Gut round table meeting. Gut 2020; 69: 764- 80.

[28] Kazankov K, Jørgensen SMD, Thomsen KL, et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol 2019; 16: 145- 59.

[29] Cai J, Zhang XJ, Li H. The role of innate immune cells in nonalcoholic steatohepatitis. Hepatology 2019; 70: 1026- 37.

[30] Hammoutene A, Rautou PE. Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease. J Hepatol 2019; 70: 1278- 91.

[31] Jonas W, Schürmann A. Genetic and epigenetic factors determining NAFLD risk. Mol Metab 2021; 50: 101111.

[32] Wu YL, Lin ZJ, Li CC, et al. Epigenetic regulation in metabolic diseases: mechanisms and advances in clinical study. Signal Transduct Target Ther 2023; 8: 98.

[33] Mattei AL, Bailly N, Meissner A. DNA methylation: a historical perspective. Trends Genet 2022; 38: 676- 707.

[34] Illingworth RS, Bird AP. CpG islands--‘a rough guide’. FEBS Lett 2009; 583: 1713- 20.

[35] Reik W, Dean W. DNA methylation and mammalian epigenetics. Electrophoresis 2001; 22: 2838- 43.

[36] Hyun J, Jung Y. DNA methylation in nonalcoholic fatty liver disease. Int J Mol Sci 2020; 21: 8138.

[37] Sookoian S, Rosselli MS, Gemma C, et al. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter. Hepatology 2010; 52: 1992- 2000.

[38] Zeybel M, Hardy T, Robinson SM, et al. Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease. Clin Epigenetics 2015; 7: 25.

[39] Hardy T, Zeybel M, Day CP, et al. Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease. Gut 2017; 66: 1321- 8.

[40] Pirola CJ, Gianotti TF, Burgueño AL, et al. Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut 2013; 62: 1356- 63.

[41] Chen G, Broséus J, Hergalant S, et al. Identification of master genes involved in liver key functions through transcriptomics and epigenomics of methyl donor deficiency in rat: relevance to nonalcoholic liver disease. Mol Nutr Food Res 2015; 59: 293- 302.

[42] Qin Y, Li B, Arumugam S, et al. m(6)A mRNA methylation-directed myeloid cell activation controls progression of NAFLD and obesity. Cell Rep 2021; 37: 109968.

[43] Johnson ND, Wu X, Still CD, et al. Differential DNA methylation and changing cell-type proportions as fibrotic stage progresses in NAFLD. Clin Epigenetics 2021; 13: 152.

[44] Shi Y, Qi W. Histone modifications in NAFLD: mechanisms and potential therapy. Int J Mol Sci 2023; 24: 14653.

[45] Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA 2015; 313: 2263- 73.

[46] Aurora AB, Biyashev D, Mirochnik Y, et al. NF-kappaB balances vascular regression and angiogenesis via chromatin remodeling and NFAT displacement. Blood 2010; 116: 475- 84.

[47] Huang HM, Fan SJ, Zhou XR, et al. Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis. Acta Pharmacol Sin 2022; 43: 941- 53.

[48] Yin Q, Li Y, Zhou Z, et al. RPA1 controls chromatin architecture and maintains lipid metabolic homeostasis. Cell Rep 2022; 40: 111071.

[49] Yang Z, Zhang S, Liu X, et al. Histone demethylase KDM1A promotes hepatic steatosis and inflammation by increasing chromatin accessibility in NAFLD. J Lipid Res 2024; 65: 100513.

[50] Lorch Y, Kornberg RD. Chromatin-remodeling for transcription. Q Rev Biophys 2017; 50: e5.

[51] O’Brien J, Hayder H, Zayed Y, et al. Overview of MicroRNA biogenesis, mechanisms of actions, and circulation. Front Endocrinol (Lausanne) 2018; 9: 402.

[52] Vienberg S, Geiger J, Madsen S, et al. MicroRNAs in metabolism. Acta Physiol (Oxf) 2017; 219: 346- 61.

[53] Gao H, Jin Z, Bandyopadhyay G, et al. MiR-690 treatment causes decreased fibrosis and steatosis and restores specific Kupffer cell functions in NASH. Cell Metab 2022; 34: 978- 90.e4.

[54] Liu XL, Pan Q, Cao HX, et al. Lipotoxic hepatocyte-derived exosomal MicroRNA 192-5p activates macrophages through Rictor/Akt/Forkhead box transcription factor O1 signaling in nonalcoholic fatty liver Disease. Hepatology 2020; 72: 454- 69.

[55] Pirola CJ, Fernández Gianotti T, Castaño GO, et al. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut 2015; 64: 800- 12.

[56] Zhang Q, Yu K, Cao Y, et al. miR-125b promotes the NF-κB-mediated inflammatory response in NAFLD via directly targeting TNFAIP3. Life Sci 2021; 270: 119071.

[57] Hou X, Yin S, Ren R, et al. Myeloid-cell-specific IL-6 signaling promotes MicroRNA-223-enriched exosome production to attenuate NAFLD-associated fibrosis. Hepatology 2021; 74: 116- 32.

[58] He Y, Hwang S, Cai Y, et al. MicroRNA-223 ameliorates nonalcoholic steatohepatitis and cancer by targeting multiple inflammatory and oncogenic genes in hepatocytes. Hepatology 2019; 70: 1150- 67.

[59] Hur W, Lee JH, Kim SW, et al. Downregulation of microRNA-451 in non-alcoholic steatohepatitis inhibits fatty acid-induced proinflammatory cytokine production through the AMPK/AKT pathway. Int J Biochem Cell Biol 2015; 64: 265- 76.

[60] Yang YL, Kuo HC, Wang FS, et al. MicroRNA-29a disrupts DNMT3b to ameliorate diet-induced non-alcoholic steatohepatitis in mice. Int J Mol Sci 2019; 20: 1499.

[61] Lin HY, Wang FS, Yang YL, et al. MicroRNA-29a suppresses CD36 to ameliorate high fat diet-induced steatohepatitis and liver fibrosis in mice. Cells 2019; 8: 1298.

[62] Mehta R, Otgonsuren M, Younoszai Z, et al. Circulating miRNA in patients with non-alcoholic fatty liver disease and coronary artery disease. BMJ Open Gastroenterol 2016; 3: e000096.

[63] Lao Y, Li Q, Li N, et al. Long noncoding RNA ENST00000455974 plays an oncogenic role through up-regulating JAG2 in human DNA mismatch repair-proficient colon cancer. Biochem Biophys Res Commun 2019; 508: 339- 47.

[64] Ding F, Lai J, Gao Y, et al. NEAT1/miR-23a-3p/KLF3: a novel regulatory axis in melanoma cancer progression. Cancer Cell Int 2019; 19: 217.

[65] Zhang CC, Niu F. LncRNA NEAT1 promotes inflammatory response in sepsis-induced liver injury via the Let-7a/TLR4 axis. Int Immunopharmacol 2019; 75: 105731.

[66] Chen X, Tan XR, Li SJ, et al. LncRNA NEAT1 promotes hepatic lipid accumulation via regulating miR-146a-5p/ROCK1 in nonalcoholic fatty liver disease. Life Sci 2019; 235: 116829.

[67] Liu L, Sun S, Li X. LncRNA ZFAS1 ameliorates injury led by nonalcoholic fatty liver disease via suppressing lipid peroxidation and inflammation. Clin Res Hepatol Gastroenterol 2023; 47: 102067.

[68] Ye L, Zhao D, Xu Y, et al. LncRNA-Gm9795 promotes inflammation in non-alcoholic steatohepatitis via NF-[Formula: see text]B/JNK pathway by endoplasmic reticulum stress. J Transl Med 2021; 19: 101.

[69] Wu B, Xu C, Tian Y, et al. Aerobic exercise promotes the expression of ATGL and attenuates inflammation to improve hepatic steatosis via lncRNA SRA. Sci Rep 2022; 12: 5370.

[70] Leti F, Legendre C, Still CD, et al. Altered expression of MALAT1 lncRNA in nonalcoholic steatohepatitis fibrosis regulates CXCL5 in hepatic stellate cells. Transl Res 2017; 190: 25- 39.e21.

[71] Atanasovska B, Rensen SS, Marsman G, et al. Long non-coding RNAs involved in progression of non-alcoholic fatty liver disease to steatohepatitis. Cells 2021; 10: 1883.

[72] Chen Y, Chen X, Gao J, et al. Long noncoding RNA FLRL2 alleviated nonalcoholic fatty liver disease through Arntl-Sirt1 pathway. FASEB J 2019; 33: 11411- 9.

[73] Kristensen LS, Andersen MS, Stagsted LVW, et al. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet 2019; 20: 675- 91.

[74] Xia Q, Ding T, Zhang G, et al. Circular RNA expression profiling identifies prostate cancer-specific circRNAs in prostate cancer. Cell Physiol Biochem 2018; 50: 1903- 15.

[75] Li J, Qi J, Tang Y, et al. A nanodrug system overexpressed cir-cRNA_0001805 alleviates nonalcoholic fatty liver disease via miR-106a-5p/miR-320a and ABCA1/CPT1 axis. J Nanobiotechnology 2021; 19: 363.

[76] Yepmo M, Potier JB, Pinget M, et al. Discussing the role of circular RNA in the pathogenesis of non-alcoholic fatty liver disease and its complications. Front Endocrinol (Lausanne) 2022; 13: 1035159.

[77] Ramezani M, Zobeiry M, Abdolahi S, et al. A crosstalk between epigenetic modulations and non-alcoholic fatty liver disease progression. Pathol Res Pract 2023; 251: 154809.

[78] Ashraf NU, Altaf M. Epigenetics: an emerging field in the pathogenesis of nonalcoholic fatty liver disease. Mutat Res Rev Mutat Res 2018; 778: 1- 12.

[79] Li YY, Tang D, Du YL, et al. Fatty liver mediated by peroxisome proliferator-activated receptor-α DNA methylation can be reversed by a methylation inhibitor and curcumin. J Dig Dis 2018; 19: 421- 30.

[80] Liu CH, Ampuero J, Gil-Gómez A, et al. miRNAs in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 2018; 69: 1335- 48.

[81] DiStefano JK, Gerhard GS. Long noncoding RNAs and human liver disease. Annu Rev Pathol 2022; 17: 1- 21.

[82] Zhao XY, Xiong X, Liu T, et al. Long noncoding RNA licensing of obesity-linked hepatic lipogenesis and NAFLD pathogenesis. Nat Commun 2018; 9: 2986.

[83] Targher G, Bertolini L, Padovani R, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among Type 2 dia betic patients. Diabetes Care 2007; 30: 1212- 8.

[84] Zhang Y, Wang H, Xiao H. Metformin actions on the liver: protection mechanisms emerging in hepatocytes and immune cells against NASH-related HCC. Int J Mol Sci 2021; 22: 5016.

RIGHTS & PERMISSIONS

2024 The Author(s). Published by Oxford University Press on behalf of Higher Education Press.