Epigenetics in Liver Fibrosis

Veronica Massey; Joaquin Cabezas; Ramon Bataller

doi:10.1055/s-0037-1605371

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2017; 37(03): 219-230
DOI: 10.1055/s-0037-1605371

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Epigenetics in Liver Fibrosis

Veronica Massey

¹Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina

,

Joaquin Cabezas

² Department of Gastroenterology and Hepatology, University Hospital Marques de Valdecilla, Santander, Spain

³Valdecilla Research Institute – IDIVAL, Santander, Spain

,

Ramon Bataller

¹Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina

⁴Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

⁵Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pennsylvania

› Author Affiliations

Abstract

Liver fibrosis is a common consequence of chronic liver injury and is a key determinant of liver-associated morbidity and mortality. Identification of new mechanisms of fibrosis, including disease-specific molecular drivers, remains relevant to reveal novel biomarkers and therapeutic targets. Recently, greater accessibility to more advanced molecular methods that can assess changes in epigenetic regulation has stimulated more research investigating the epigenetic landscape of liver fibrosis. Such studies have revealed changes in DNA methylation, histone acetylation, and microRNAs that regulate the fibrogenic response to injury including hepatic stellate cell activation. The aim of this review is to briefly introduce the general mechanisms and epigenetic regulation of liver fibrosis and to familiarize the reader with the chief epigenetic mechanisms implicated as drivers of liver fibrosis.

Keywords

epigenetics - hepatic fibrosis - liver disease

Full Text

References

References
1 Mann J, Chu DC, Maxwell A. , et al. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 2010; 138 (02) 705-714 , 714.e1–714.e4
2 Mannaerts I, Nuytten NR, Rogiers V, Vanderkerken K, van Grunsven LA, Geerts A. Chronic administration of valproic acid inhibits activation of mouse hepatic stellate cells in vitro and in vivo. Hepatology 2010; 51 (02) 603-614
3 Niki T, Rombouts K, De Bleser P. , et al. A histone deacetylase inhibitor, trichostatin A, suppresses myofibroblastic differentiation of rat hepatic stellate cells in primary culture. Hepatology 1999; 29 (03) 858-867
4 Ahuja N, Sharma AR, Baylin SB. Epigenetic therapeutics: a new weapon in the war against cancer. Annu Rev Med 2016; 67: 73-89
5 Morera L, Lübbert M, Jung M. Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin Epigenetics 2016; 8: 57
6 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 (05) 1547-1554
7 Lackner C, Spindelboeck W, Haybaeck J. , et al. Histological parameters and alcohol abstinence determine long-term prognosis in patients with alcoholic liver disease. J Hepatol 2017; 66 (03) 610-618
8 Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997; 349 (9055): 825-832
9 Poynard T, Ratziu V, Benhamou Y, Opolon P, Cacoub P, Bedossa P. Natural history of HCV infection. Best Pract Res Clin Gastroenterol 2000; 14 (02) 211-228
10 Bataller R, North KE, Brenner DA. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology 2003; 37 (03) 493-503
11 Huang H, Shiffman ML, Friedman S. , et al. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology 2007; 46 (02) 297-306
12 Bataller R, Brenner DA. Hepatic stellate cells as a target for the treatment of liver fibrosis. Semin Liver Dis 2001; 21 (03) 437-451
13 Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115 (02) 209-218
14 Koyama Y, Brenner DA. New therapies for hepatic fibrosis. Clin Res Hepatol Gastroenterol 2015; 39 (Suppl. 01) S75-S79
15 Geerts A. History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis 2001; 21 (03) 311-335
16 Mederacke I, Hsu CC, Troeger JS. , et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 2013; 4: 2823
17 Wells RG, Schwabe RF. Origin and function of myofibroblasts in the liver. Semin Liver Dis 2015; 35 (02) 97-106
18 Koyama Y, Wang P, Liang S. , et al. Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis. J Clin Invest 2017; 127 (04) 1254-1270
19 Forbes SJ, Russo FP, Rey V. , et al. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 2004; 126 (04) 955-963
20 Ramadori G, Saile B. Portal tract fibrogenesis in the liver. Lab Invest 2004; 84 (02) 153-159
21 Naito M, Hasegawa G, Ebe Y, Yamamoto T. Differentiation and function of Kupffer cells. Med Electron Microsc 2004; 37 (01) 16-28
22 Thurman RG. II. Alcoholic liver injury involves activation of Kupffer cells by endotoxin. Am J Physiol 1998; 275 (4 Pt 1): G605-G611
23 Shi Z, Wakil AE, Rockey DC. Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses. Proc Natl Acad Sci U S A 1997; 94 (20) 10663-10668
24 Mehal WZ, Friedman SL. The role of inflammation and immunity in the pathogenesis of liver fibrosis. In: Gershwin ME, Vierling JM, Manns MP. , eds. Liver Immunology: Principles and Practice. Totowa, NJ: Humana Press; 2007: 111-121
25 Greuter T, Shah VH. Hepatic sinusoids in liver injury, inflammation, and fibrosis: new pathophysiological insights. J Gastroenterol 2016; 51 (06) 511-519
26 Kinnman N, Housset C. Peribiliary myofibroblasts in biliary type liver fibrosis. Front Biosci 2002; 7: d496-d503
27 Maher JJ. Interactions between hepatic stellate cells and the immune system. Semin Liver Dis 2001; 21 (03) 417-426
28 Kmieć Z. Cooperation of liver cells in health and disease. Adv Anat Embryol Cell Biol 2001; 161: III-XIII , 1–151
29 Annoni G, Weiner FR, Zern MA. Increased transforming growth factor-beta 1 gene expression in human liver disease. J Hepatol 1992; 14 (2-3): 259-264
30 Castilla A, Prieto J, Fausto N. Transforming growth factors beta 1 and alpha in chronic liver disease. Effects of interferon alfa therapy. N Engl J Med 1991; 324 (14) 933-940
31 Gressner AM, Weiskirchen R, Breitkopf K, Dooley S. Roles of TGF-beta in hepatic fibrosis. Front Biosci 2002; 7: d793-d807
32 Malizia G, Brunt EM, Peters MG, Rizzo A, Broekelmann TJ, McDonald JA. Growth factor and procollagen type I gene expression in human liver disease. Gastroenterology 1995; 108 (01) 145-156
33 Dooley S, Hamzavi J, Breitkopf K. , et al. Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats. Gastroenterology 2003; 125 (01) 178-191
34 Schnabl B, Kweon YO, Frederick JP, Wang XF, Rippe RA, Brenner DA. The role of Smad3 in mediating mouse hepatic stellate cell activation. Hepatology 2001; 34 (01) 89-100
35 Inagaki Y, Okazaki I. Emerging insights into Transforming growth factor beta Smad signal in hepatic fibrogenesis. Gut 2007; 56 (02) 284-292
36 Liu C, Gaça MD, Swenson ES, Vellucci VF, Reiss M, Wells RG. Smads 2 and 3 are differentially activated by transforming growth factor-beta (TGF-beta) in quiescent and activated hepatic stellate cells. Constitutive nuclear localization of Smads in activated cells is TGF-beta-independent. J Biol Chem 2003; 278 (13) 11721-11728
37 Dooley S, Delvoux B, Lahme B, Mangasser-Stephan K, Gressner AM. Modulation of transforming growth factor beta response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts. Hepatology 2000; 31 (05) 1094-1106
38 Inagaki Y, Truter S, Greenwel P. , et al. Regulation of the alpha 2(I) collagen gene transcription in fat-storing cells derived from a cirrhotic liver. Hepatology 1995; 22 (02) 573-579
39 Nieto N, Dominguez-Rosales JA, Fontana L. , et al. Rat hepatic stellate cells contribute to the acute-phase response with increased expression of alpha1(I) and alpha1(IV) collagens, tissue inhibitor of metalloproteinase-1, and matrix-metalloproteinase-2 messenger RNAs. Hepatology 2001; 33 (03) 597-607
40 Hazra S, Miyahara T, Rippe RA, Tsukamoto H. PPAR gamma and hepatic stellate cells. Comp Hepatol 2004; 3 (Suppl. 01) S7
41 Sun K, Wang Q, Huang XH. PPAR gamma inhibits growth of rat hepatic stellate cells and TGF beta-induced connective tissue growth factor expression. Acta Pharmacol Sin 2006; 27 (06) 715-723
42 Galli A, Crabb DW, Ceni E. , et al. Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology 2002; 122 (07) 1924-1940
43 Marra F, Efsen E, Romanelli RG. , et al. Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology 2000; 119 (02) 466-478
44 Marra F. Leptin and liver fibrosis: a matter of fat. Gastroenterology 2002; 122 (05) 1529-1532
45 Bataller R, Ginès P, Nicolás JM. , et al. Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology 2000; 118 (06) 1149-1156
46 Jonsson JR, Clouston AD, Ando Y. , et al. Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis. Gastroenterology 2001; 121 (01) 148-155
47 Paizis G, Gilbert RE, Cooper ME. , et al. Effect of angiotensin II type 1 receptor blockade on experimental hepatic fibrogenesis. J Hepatol 2001; 35 (03) 376-385
48 Oben JA, Roskams T, Yang S. , et al. Hepatic fibrogenesis requires sympathetic neurotransmitters. Gut 2004; 53 (03) 438-445
49 Williams EJ, Benyon RC, Trim N. , et al. Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo. Gut 2001; 49 (04) 577-583
50 Degoul F, Sutton A, Mansouri A. , et al. Homozygosity for alanine in the mitochondrial targeting sequence of superoxide dismutase and risk for severe alcoholic liver disease. Gastroenterology 2001; 120 (06) 1468-1474
51 Donaldson P, Agarwal K, Craggs A, Craig W, James O, Jones D. HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: associations with disease progression and disease susceptibility. Gut 2001; 48 (03) 397-402
52 Järveläinen HA, Orpana A, Perola M, Savolainen VT, Karhunen PJ, Lindros KO. Promoter polymorphism of the CD14 endotoxin receptor gene as a risk factor for alcoholic liver disease. Hepatology 2001; 33 (05) 1148-1153
53 Akuta N, Chayama K, Suzuki F. , et al. Risk factors of hepatitis C virus-related liver cirrhosis in young adults: positive family history of liver disease and transporter associated with antigen processing 2(TAP2)*0201 Allele. J Med Virol 2001; 64 (02) 109-116
54 Dixon JB, Bhathal PS, Jonsson JR, Dixon AF, Powell EE, O'Brien PE. Pro-fibrotic polymorphisms predictive of advanced liver fibrosis in the severely obese. J Hepatol 2003; 39 (06) 967-971
55 Powell EE, Edwards-Smith CJ, Hay JL. , et al. Host genetic factors influence disease progression in chronic hepatitis C. Hepatology 2000; 31 (04) 828-833
56 Sasaki K, Tsutsumi A, Wakamiya N. , et al. Mannose-binding lectin polymorphisms in patients with hepatitis C virus infection. Scand J Gastroenterol 2000; 35 (09) 960-965
57 Yoneda M, Hotta K, Nozaki Y. , et al. Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease. Liver Int 2009; 29 (07) 1078-1085
58 Romeo S, Kozlitina J, Xing C. , et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40 (12) 1461-1465
59 Stickel F, Buch S, Lau K. , et al. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in Caucasians. Hepatology 2011; 53 (01) 86-95
60 Tian C, Stokowski RP, Kershenobich D, Ballinger DG, Hinds DA. Variant in PNPLA3 is associated with alcoholic liver disease. Nat Genet 2010; 42 (01) 21-23
61 Waddington CH. The epigenotype. 1942. Int J Epidemiol 2012; 41 (01) 10-13
62 Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell 2007; 128 (04) 635-638
63 Zhu H, Wang G, Qian J. Transcription factors as readers and effectors of DNA methylation. Nat Rev Genet 2016; 17 (09) 551-565
64 Bogdanović O, Veenstra GJ. DNA methylation and methyl-CpG binding proteins: developmental requirements and function. Chromosoma 2009; 118 (05) 549-565
65 Szulwach KE, Jin P. Integrating DNA methylation dynamics into a framework for understanding epigenetic codes. BioEssays 2014; 36 (01) 107-117
66 Jurkowska RZ, Jurkowski TP, Jeltsch A. Structure and function of mammalian DNA methyltransferases. ChemBioChem 2011; 12 (02) 206-222
67 Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu Rev Biochem 2005; 74: 481-514
68 Arita K, Ariyoshi M, Tochio H, Nakamura Y, Shirakawa M. Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism. Nature 2008; 455 (7214): 818-821
69 Qian C, Li S, Jakoncic J, Zeng L, Walsh MJ, Zhou MM. Structure and hemimethylated CpG binding of the SRA domain from human UHRF1. J Biol Chem 2008; 283 (50) 34490-34494
70 Tahiliani M, Koh KP, Shen Y. , et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009; 324 (5929): 930-935
71 Mellén M, Ayata P, Dewell S, Kriaucionis S, Heintz N. MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 2012; 151 (07) 1417-1430
72 Iurlaro M, Ficz G, Oxley D. , et al. A screen for hydroxymethylcytosine and formylcytosine binding proteins suggests functions in transcription and chromatin regulation. Genome Biol 2013; 14 (10) R119
73 Saha A, Wittmeyer J, Cairns BR. Chromatin remodelling: the industrial revolution of DNA around histones. Nat Rev Mol Cell Biol 2006; 7 (06) 437-447
74 Chahal SS, Matthews HR, Bradbury EM. Acetylation of histone H4 and its role in chromatin structure and function. Nature 1980; 287 (5777): 76-79
75 Tropberger P, Pott S, Keller C. , et al. Regulation of transcription through acetylation of H3K122 on the lateral surface of the histone octamer. Cell 2013; 152 (04) 859-872
76 Tse C, Sera T, Wolffe AP, Hansen JC. Disruption of higher-order folding by core histone acetylation dramatically enhances transcription of nucleosomal arrays by RNA polymerase III. Mol Cell Biol 1998; 18 (08) 4629-4638
77 Neumann H, Hancock SM, Buning R. , et al. A method for genetically installing site-specific acetylation in recombinant histones defines the effects of H3 K56 acetylation. Mol Cell 2009; 36 (01) 153-163
78 Hassan AH, Prochasson P, Neely KE. , et al. Function and selectivity of bromodomains in anchoring chromatin-modifying complexes to promoter nucleosomes. Cell 2002; 111 (03) 369-379
79 Huang Y, Fang J, Bedford MT, Zhang Y, Xu RM. Recognition of histone H3 lysine-4 methylation by the double Tudor domain of JMJD2A. Science 2006; 312 (5774): 748-751
80 Blackledge NP, Rose NR, Klose RJ. Targeting Polycomb systems to regulate gene expression: modifications to a complex story. Nat Rev Mol Cell Biol 2015; 16 (11) 643-649
81 Di Croce L, Helin K. Transcriptional regulation by Polycomb group proteins. Nat Struct Mol Biol 2013; 20 (10) 1147-1155
82 Ku M, Koche RP, Rheinbay E. , et al. Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS Genet 2008; 4 (10) e1000242
83 Lynch MD, Smith AJ, De Gobbi M. , et al. An interspecies analysis reveals a key role for unmethylated CpG dinucleotides in vertebrate Polycomb complex recruitment. EMBO J 2012; 31 (02) 317-329
84 Mendenhall EM, Koche RP, Truong T. , et al. GC-rich sequence elements recruit PRC2 in mammalian ES cells. PLoS Genet 2010; 6 (12) e1001244
85 Tanay A, O'Donnell AH, Damelin M, Bestor TH. Hyperconserved CpG domains underlie Polycomb-binding sites. Proc Natl Acad Sci U S A 2007; 104 (13) 5521-5526
86 Hansen KH, Bracken AP, Pasini D. , et al. A model for transmission of the H3K27me3 epigenetic mark. Nat Cell Biol 2008; 10 (11) 1291-1300
87 Margueron R, Justin N, Ohno K. , et al. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 2009; 461 (7265): 762-767
88 Arnold P, Schöler A, Pachkov M. , et al. Modeling of epigenome dynamics identifies transcription factors that mediate Polycomb targeting. Genome Res 2013; 23 (01) 60-73
89 Brockdorff N. Noncoding RNA and Polycomb recruitment. RNA 2013; 19 (04) 429-442
90 Venkatesh S, Workman JL. Histone exchange, chromatin structure and the regulation of transcription. Nat Rev Mol Cell Biol 2015; 16 (03) 178-189
91 Kasten M, Szerlong H, Erdjument-Bromage H, Tempst P, Werner M, Cairns BR. Tandem bromodomains in the chromatin remodeler RSC recognize acetylated histone H3 Lys14. EMBO J 2004; 23 (06) 1348-1359
92 Weber CM, Henikoff S. Histone variants: dynamic punctuation in transcription. Genes Dev 2014; 28 (07) 672-682
93 Conerly ML, Teves SS, Diolaiti D, Ulrich M, Eisenman RN, Henikoff S. Changes in H2A.Z occupancy and DNA methylation during B-cell lymphomagenesis. Genome Res 2010; 20 (10) 1383-1390
94 Zilberman D, Coleman-Derr D, Ballinger T, Henikoff S. Histone H2A.Z and DNA methylation are mutually antagonistic chromatin marks. Nature 2008; 456 (7218): 125-129
95 Li B, Pattenden SG, Lee D. , et al. Preferential occupancy of histone variant H2AZ at inactive promoters influences local histone modifications and chromatin remodeling. Proc Natl Acad Sci U S A 2005; 102 (51) 18385-18390
96 Swaminathan J, Baxter EM, Corces VG. The role of histone H2Av variant replacement and histone H4 acetylation in the establishment of Drosophila heterochromatin. Genes Dev 2005; 19 (01) 65-76
97 Jin C, Felsenfeld G. Nucleosome stability mediated by histone variants H3.3 and H2A.Z. Genes Dev 2007; 21 (12) 1519-1529
98 Zhang H, Roberts DN, Cairns BR. Genome-wide dynamics of Htz1, a histone H2A variant that poises repressed/basal promoters for activation through histone loss. Cell 2005; 123 (02) 219-231
99 Jonas S, Izaurralde E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat Rev Genet 2015; 16 (07) 421-433
100 Lam JK, Chow MY, Zhang Y, Leung SW. siRNA versus miRNA as therapeutics for gene silencing. Mol Ther Nucleic Acids 2015; 4: e252
101 Aravin AA, Sachidanandam R, Bourc'his D. , et al. A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. Mol Cell 2008; 31 (06) 785-799
102 Watanabe T, Tomizawa S, Mitsuya K. , et al. Role for piRNAs and noncoding RNA in de novo DNA methylation of the imprinted mouse Rasgrf1 locus. Science 2011; 332 (6031): 848-852
103 Mohammad F, Mondal T, Guseva N, Pandey GK, Kanduri C. Kcnq1ot1 noncoding RNA mediates transcriptional gene silencing by interacting with Dnmt1. Development 2010; 137 (15) 2493-2499
104 Peschansky VJ, Wahlestedt C. Non-coding RNAs as direct and indirect modulators of epigenetic regulation. Epigenetics 2014; 9 (01) 3-12
105 Latos PA, Pauler FM, Koerner MV. , et al. Airn transcriptional overlap, but not its lncRNA products, induces imprinted Igf2r silencing. Science 2012; 338 (6113): 1469-1472
106 Murphy SK, Yang H, Moylan CA. , et al. Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease. Gastroenterology 2013; 145 (05) 1076-1087
107 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
108 El Taghdouini A, Sørensen AL, Reiner AH. , et al. Genome-wide analysis of DNA methylation and gene expression patterns in purified, uncultured human liver cells and activated hepatic stellate cells. Oncotarget 2015; 6 (29) 26729-26745
109 Komatsu Y, Waku T, Iwasaki N, Ono W, Yamaguchi C, Yanagisawa J. Global analysis of DNA methylation in early-stage liver fibrosis. BMC Med Genomics 2012; 5: 5
110 Page A, Paoli P, Moran Salvador E, White S, French J, Mann J. Hepatic stellate cell transdifferentiation involves genome-wide remodeling of the DNA methylation landscape. J Hepatol 2016; 64 (03) 661-673
111 Asada K, Aihara Y, Takaya H. , et al. DNA methylation of angiotensin II receptor gene in nonalcoholic steatohepatitis-related liver fibrosis. World J Hepatol 2016; 8 (28) 1194-1199
112 Bian EB, Huang C, Ma TT. , et al. DNMT1-mediated PTEN hypermethylation confers hepatic stellate cell activation and liver fibrogenesis in rats. Toxicol Appl Pharmacol 2012; 264 (01) 13-22
113 Bian EB, Huang C, Wang H. , et al. Repression of Smad7 mediated by DNMT1 determines hepatic stellate cell activation and liver fibrosis in rats. Toxicol Lett 2014; 224 (02) 175-185
114 Tao H, Huang C, Yang JJ. , et al. MeCP2 controls the expression of RASAL1 in the hepatic fibrosis in rats. Toxicology 2011; 290 (2-3): 327-333
115 Wu K, Ye C, Lin L. , et al. Inhibiting miR-21 attenuates experimental hepatic fibrosis by suppressing both the ERK1 pathway in HSC and hepatocyte EMT. Clin Sci (Lond) 2016; 130 (16) 1469-1480
116 Mann J, Oakley F, Akiboye F, Elsharkawy A, Thorne AW, Mann DA. Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis. Cell Death Differ 2007; 14 (02) 275-285
117 Yang JJ, Tao H, Huang C. , et al. DNA methylation and MeCP2 regulation of PTCH1 expression during rats hepatic fibrosis. Cell Signal 2013; 25 (05) 1202-1211
118 Zhu NL, Wang J, Tsukamoto H. The Necdin-Wnt pathway causes epigenetic peroxisome proliferator-activated receptor gamma repression in hepatic stellate cells. J Biol Chem 2010; 285 (40) 30463-30471
119 Jiang Y, Wang S, Zhao Y. , et al. Histone H3K9 demethylase JMJD1A modulates hepatic stellate cells activation and liver fibrosis by epigenetically regulating peroxisome proliferator-activated receptor γ. FASEB J 2015; 29 (05) 1830-1841
120 Perugorria MJ, Wilson CL, Zeybel M. , et al. Histone methyltransferase ASH1 orchestrates fibrogenic gene transcription during myofibroblast transdifferentiation. Hepatology 2012; 56 (03) 1129-1139
121 Kim JS, Shukla SD. Histone h3 modifications in rat hepatic stellate cells by ethanol. Alcohol Alcohol 2005; 40 (05) 367-372
122 Watanabe T, Tajima H, Hironori H. , et al. Sodium valproate blocks the transforming growth factor (TGF)-β1 autocrine loop and attenuates the TGF-β1-induced collagen synthesis in a human hepatic stellate cell line. Int J Mol Med 2011; 28 (06) 919-925
123 Westra IM, Oosterhuis D, Groothuis GM, Olinga P. The effect of antifibrotic drugs in rat precision-cut fibrotic liver slices. PLoS One 2014; 9 (04) e95462
124 Liu Y, Wang Z, Wang J. , et al. A histone deacetylase inhibitor, largazole, decreases liver fibrosis and angiogenesis by inhibiting transforming growth factor-β and vascular endothelial growth factor signalling. Liver Int 2013; 33 (04) 504-515
125 Park KC, Park JH, Jeon JY. , et al. A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells. Br J Pharmacol 2014; 171 (21) 4820-4830
126 Li X, Wu XQ, Xu T. , et al. Role of histone deacetylases(HDACs) in progression and reversal of liver fibrosis. Toxicol Appl Pharmacol 2016; 306: 58-68
127 Qin L, Han YP. Epigenetic repression of matrix metalloproteinases in myofibroblastic hepatic stellate cells through histone deacetylases 4: implication in tissue fibrosis. Am J Pathol 2010; 177 (04) 1915-1928
128 Bai X, Wu L, Liang T. , et al. Overexpression of myocyte enhancer factor 2 and histone hyperacetylation in hepatocellular carcinoma. J Cancer Res Clin Oncol 2008; 134 (01) 83-91
129 Harikrishnan KN, Chow MZ, Baker EK. , et al. Brahma links the SWI/SNF chromatin-remodeling complex with MeCP2-dependent transcriptional silencing. Nat Genet 2005; 37 (03) 254-264
130 Tian W, Xu H, Fang F, Chen Q, Xu Y, Shen A. Brahma-related gene 1 bridges epigenetic regulation of proinflammatory cytokine production to steatohepatitis in mice. Hepatology 2013; 58 (02) 576-588
131 Xi Q, He W, Zhang XH, Le HV, Massagué J. Genome-wide impact of the BRG1 SWI/SNF chromatin remodeler on the transforming growth factor beta transcriptional program. J Biol Chem 2008; 283 (02) 1146-1155
132 Zhang Z, Zha Y, Hu W. , et al. The autoregulatory feedback loop of microRNA-21/programmed cell death protein 4/activation protein-1 (MiR-21/PDCD4/AP-1) as a driving force for hepatic fibrosis development. J Biol Chem 2013; 288 (52) 37082-37093
133 Wei J, Feng L, Li Z, Xu G, Fan X. MicroRNA-21 activates hepatic stellate cells via PTEN/Akt signaling. Biomed Pharmacother 2013; 67 (05) 387-392
134 Zhao J, Tang N, Wu K. , et al. MiR-21 simultaneously regulates ERK1 signaling in HSC activation and hepatocyte EMT in hepatic fibrosis. PLoS One 2014; 9 (10) e108005
135 Li X, Chen Y, Wu S. , et al. microRNA-34a and microRNA-34c promote the activation of human hepatic stellate cells by targeting peroxisome proliferator-activated receptor γ. Mol Med Rep 2015; 11 (02) 1017-1024
136 Li ZJ, Ou-Yang PH, Han XP. Profibrotic effect of miR-33a with Akt activation in hepatic stellate cells. Cell Signal 2014; 26 (01) 141-148
137 Lu L, Wang J, Lu H. , et al. MicroRNA-130a and -130b enhance activation of hepatic stellate cells by suppressing PPARγ expression: A rat fibrosis model study. Biochem Biophys Res Commun 2015; 465 (03) 387-393
138 Tiao MM, Wang FS, Huang LT. , et al. MicroRNA-29a protects against acute liver injury in a mouse model of obstructive jaundice via inhibition of the extrinsic apoptosis pathway. Apoptosis 2014; 19 (01) 30-41
139 Kwiecinski M, Elfimova N, Noetel A. , et al. Expression of platelet-derived growth factor-C and insulin-like growth factor I in hepatic stellate cells is inhibited by miR-29. Lab Invest 2012; 92 (07) 978-987
140 Kwiecinski M, Noetel A, Elfimova N. , et al. Hepatocyte growth factor (HGF) inhibits collagen I and IV synthesis in hepatic stellate cells by miRNA-29 induction. PLoS One 2011; 6 (09) e24568
141 Zhang Y, Ghazwani M, Li J. , et al. MiR-29b inhibits collagen maturation in hepatic stellate cells through down-regulating the expression of HSP47 and lysyl oxidase. Biochem Biophys Res Commun 2014; 446 (04) 940-944
142 Liang C, Bu S, Fan X. Suppressive effect of microRNA-29b on hepatic stellate cell activation and its crosstalk with TGF-β1/Smad3. Cell Biochem Funct 2016; 34 (05) 326-333
143 Li J, Ghazwani M, Zhang Y. , et al. miR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression. J Hepatol 2013; 58 (03) 522-528
144 Zeng C, Wang YL, Xie C. , et al. Identification of a novel TGF-β-miR-122-fibronectin 1/serum response factor signaling cascade and its implication in hepatic fibrogenesis. Oncotarget 2015; 6 (14) 12224-12233
145 Lakner AM, Steuerwald NM, Walling TL. , et al. Inhibitory effects of microRNA 19b in hepatic stellate cell-mediated fibrogenesis. Hepatology 2012; 56 (01) 300-310
146 Ge S, Xie J, Liu F, He J, He J. MicroRNA-19b reduces hepatic stellate cell proliferation by targeting GRB2 in hepatic fibrosis models in vivo and in vitro as part of the inhibitory effect of estradiol. J Cell Biochem 2015; 116 (11) 2455-2464
147 Du J, Niu X, Wang Y. , et al. MiR-146a-5p suppresses activation and proliferation of hepatic stellate cells in nonalcoholic fibrosing steatohepatitis through directly targeting Wnt1 and Wnt5a. Sci Rep 2015; 5: 16163
148 He Y, Huang C, Sun X, Long XR, Lv XW, Li J. MicroRNA-146a modulates TGF-beta1-induced hepatic stellate cell proliferation by targeting SMAD4. Cell Signal 2012; 24 (10) 1923-1930
149 Sekiya Y, Ogawa T, Iizuka M, Yoshizato K, Ikeda K, Kawada N. Down-regulation of cyclin E1 expression by microRNA-195 accounts for interferon-β-induced inhibition of hepatic stellate cell proliferation. J Cell Physiol 2011; 226 (10) 2535-2542
150 Dai W, Zhao J, Tang N. , et al. MicroRNA-155 attenuates activation of hepatic stellate cell by simultaneously preventing EMT process and ERK1 signalling pathway. Liver Int 2015; 35 (04) 1234-1243
151 Zheng J, Yu F, Dong P. , et al. Long non-coding RNA PVT1 activates hepatic stellate cells through competitively binding microRNA-152. Oncotarget 2016; 7 (39) 62886-62897
152 Yu F, Lu Z, Chen B, Dong P, Zheng J. Identification of a novel lincRNA-p21-miR-181b-PTEN signaling cascade in liver fibrosis. Mediators Inflamm 2016; 2016: 9856538
153 Yu F, Zheng J, Mao Y. , et al. Long non-coding RNA growth arrest-specific transcript 5 (GAS5) inhibits liver fibrogenesis through a mechanism of competing endogenous RNA. J Biol Chem 2015; 290 (47) 28286-28298
154 He Y, Wu YT, Huang C. , et al. Inhibitory effects of long noncoding RNA MEG3 on hepatic stellate cells activation and liver fibrogenesis. Biochim Biophys Acta 2014; 1842 (11) 2204-2215
155 Hardy T, Mann DA. Epigenetics in liver disease: from biology to therapeutics. Gut 2016; 65 (11) 1895-1905
156 Farinelli E, Giampaoli D, Cenciarini A, Cercado E, Verrotti A. Valproic acid and nonalcoholic fatty liver disease: a possible association?. World J Hepatol 2015; 7 (09) 1251-1257
157 Ikura Y, Iwasa Y, Ueda M. Valproic acid administration for hepatic fibrosis: a balance between antifibrotic efficacy and hepatotoxicity. Hepatology 2010; 51 (06) 2227-2228 , author reply 2228
158 Sato K, Ueda Y, Ueno K, Okamoto K, Iizuka H, Katsuda S. Hepatocellular carcinoma and nonalcoholic steatohepatitis developing during long-term administration of valproic acid. Virchows Arch 2005; 447 (06) 996-999
159 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 [Published Online First]. 2016 : Available at: http://gut.bmj.com/content/early/2016/2003/2021/gutjnl-2016-311526.long . Accessed October 28th, 2016
160 Huang J, Yu X, Fries JW, Zhang L, Odenthal M. MicroRNA function in the profibrogenic interplay upon chronic liver disease. Int J Mol Sci 2014; 15 (06) 9360-9371
161 Page A, Paoli PP, Hill SJ. , et al. Alcohol directly stimulates epigenetic modifications in hepatic stellate cells. J Hepatol 2015; 62 (02) 388-397
162 Roderburg C, Urban GW, Bettermann K. , et al. Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology 2011; 53 (01) 209-218
163 Zhang J, Jiao J, Cermelli S. , et al. miR-21 inhibition reduces liver fibrosis and prevents tumor development by inducing apoptosis of CD24+ progenitor cells. Cancer Res 2015; 75 (09) 1859-1867