Reversibility and heritability of liver fibrosis: Implications for research and therapy

Table 1 Summary of studies evaluating DNA methylation in liver fibrosis

Ref.	Model	Findings
Komatsu et al[23]	Mouse, early fibrosis (2 wk CCl4)	global and Spp1 promoter hypomethylation
Tao et al[17]	Rat (12 wk CCl4) and HSC-T6 cell line	5-aza-2’-deoxycytidine inhibited HSC proliferation and blocked the decreased expressions of RASAL1
Mann et al[24]	Rat (5 wk CCl4) HSC and human HSC line	5-aza-2’-deoxycytidine blocked HSC transdifferentiation and prevented loss of PPARγ expression
Zeybel et al[12]	Human NAFLD	PPARγ promoter hypermethylation in severe more than mild fibrosis
Oh et al[25]	Human cirrhotic and HCC tissues	Increased DNMT3a mRNA and hypermeyhylated cell cycle and tumor suppressor genes in cirrhotic but less than in HCC tissues

NAFLD: Non-alcoholic fatty-liver disease; HCC: Hepatocellular carcinoma.

Table 2 Summary of studies evaluating lysine methylation in liver fibrosis

Histone mark	Function	Ref.
H3K9me3 H3K27me3	MeCP2 binds to the 5' end of PPARγ and promotes methylation of H3K9. MeCP2 stimulates expression of EZH2 and methylation of H3K27 to form a repressive chromatin structure in the 3' exons of PPARγ	Mann et al[16]
H3K9me2	Repression of IκBα promoter. 5-azadC treatment of aHSCs increased expression of IκBα and protein	Mann et al[24]
H3K4	ASH1 (H3K4 methyltransferase) binds to promoters and 5' end of αSMA, collagen I, TIMP-1 and TGFβ-1 in aHSCs resulting in transcriptional activation of gene expression	Perugorria et al[33]
H3K4 H3K27	ASH1 and EZH2 lysin methyltransferases that regualte H3K4 and H3K27 methylation, respectively were upregulated during liver fibrosis progression and downregulated during fibrosis resolution	Atta et al[32]

Table 3 Summary of recent studies evaluating role of miRNA in liver fibrosis

miRNA	Function	Ref.
miR-15b/16	Downregulated in aHSCs. Restoring miR-16 and miR-15b reduced Bcl-2, and increased expression of caspases 3, 8, and 9 and aHSC apoptosis	Guo et al[87]
miR-19b	Downregulated in aHSCs and in human fibrotic liver. miR-19b binds to the 3'-UTR of TGF-βRII. miR-19b mimic decreases expression of TGF-βRII, collagen and α-SMA and increases quiescent characteristics	Lakner et al[44]
miR-21	Upregulated in PDGF-BB-aHSCs through PTEN/Akt pathway	Wei et al[88]
miR-21	Upregulated in cirrhotic patients and rats. Targets the 3'-UTR of SPRY2 and HNF4α mRNAs in human and rat. Downregulating miR-21 suppressed ERK1 signaling, inhibited HSC activation, and blocked EMT in TGFβ1-treated hepatocytes	Zhao et al[45]
miR-27a/b	Upregulated in cultured-aHSCs. Downregulation of miR-27a/b induced quiesent HSC phenotype. Target Retinoid X receptor α (RXRα)	Ji et al[46]
miR-29a/b/c	Decreased expression in murine and human fibrotic livers. Serum expression negatively correlated with degree of liver fibrosis in humans	Roderburg et al[48]
miR-29b	miR-29b overexpression suppressed Col1α1 mRNA and protein	Ogawa et al[43]
miR-29b	Downregulated during HSC activation in primary culture. miR-29 overexpression attenuated the increased expression of Col1α1 and Col1α2, α-SMA, DDR2, FN1, ITGB1, and PDGFR-β mRNAs, inhibited HSC activation and supressed c-fos mRNA	Sekiya et al[47]
miR-122	Downregulated in HCV-induced liver fibrosis. Expression inversly correlated with fibrosis stage	Morita et al[89]
miR-132	Downregulated in aHSCs. In quiescent HSCs miR-132 binds and represses MeCP2 transcripts that carry an extended 3'-UTR that includes the miR132 recognition motif. MeCP promotes methylation of H3K27 of PPARγ through stimulation of EZH2	Mann et al[16]
miR-150, miR-194	Both are reduced in aHScs. miR-150 targets c-myb and miR-194 targets rac-1. Both inhibit HSC activation and ECM production via inhibition of c-myb and rac-1	Venugopal et al[90]
miR-155	Decreased expression in aHSCs, sera and liver tissues of cirrhotic patients. MiR-155 interacts with 3'-UTR of TCF4 and AGTR1 mRNAs involved in EMT and ERK1 pathway, repectively	Dai et al[50]
miR-199/200	Expression correlated to progression of liver fibrosis	Murakami et al[91]
miR-214-5p	Upregulated in human and mouse fibrotic liver	Iizuka et al[92]
miR-221/222	Upregulated in human liver in a fibrosis progression-dependent manner	Ogawa et al[93]
miR-335	Downregulated during HSC activation. Restoring expression of miR-335 inhibited HSC migration and reduced α-SMA and collagen type I	Chen et al[94]

HSC: Hepatic stellate cell; 3'-UTR: 3'-Untranslated region.