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Salvianolic acid B-induced microRNA-152 inhibits liver fibrosis by attenuating DNMT1-mediated Patched1 methylation.

Abstract
Epithelial-mesenchymal transition (EMT) was reported to be involved in the activation of hepatic stellate cells (HSCs), contributing to the development of liver fibrosis. Epithelial-mesenchymal transition can be promoted by the Hedgehog (Hh) pathway. Patched1 (PTCH1), a negative regulatory factor of the Hh signalling pathway, was down-regulated during liver fibrosis and associated with its hypermethylation status. MicroRNAs (miRNAs) are reported to play a critical role in the control of various HSCs functions. However, miRNA-mediated epigenetic regulations in EMT during liver fibrosis are seldom studied. In this study, Salvianolic acid B (Sal B) suppressed the activation of HSCs in CCl4 -treated mice and mouse primary HSCs, leading to inhibition of cell proliferation, type I collagen and alpha-smooth muscle actin. We demonstrated that the antifibrotic effects caused by Sal B were, at least in part, via inhibition of EMT and the Hh pathway. In particular, up-regulation of PTCH1 was associated with decreased DNA methylation level after Sal B treatment. Accordingly, DNA methyltransferase 1 (DNMT1) was attenuated by Sal B in vivo and in vitro. The knockdown of DNMT1 in Sal B-treated HSCs enhanced PTCH1 expression and its demethylation level. Interestingly, increased miR-152 in Sal B-treated cells was responsible for the hypomethylation of PTCH1 by Sal B. As confirmed by the luciferase activity assay, DNMT1 was a direct target of miR-152. Further studies showed that the miR-152 inhibitor reversed Sal B-mediated PTCH1 up-regulation and DNMT1 down-regulation. Collectively, miR-152 induced by Sal B, contributed to DNMT1 down-regulation and epigenetically regulated PTCH1, resulting in the inhibition of EMT in liver fibrosis.
AuthorsFujun Yu, Zhongqiu Lu, Bicheng Chen, Xiaoli Wu, Peihong Dong, Jianjian Zheng
JournalJournal of cellular and molecular medicine (J Cell Mol Med) Vol. 19 Issue 11 Pg. 2617-32 (Nov 2015) ISSN: 1582-4934 [Electronic] England
PMID26257392 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
Chemical References
  • Benzofurans
  • Dmap1 protein, mouse
  • MIRN152 microRNA, mouse
  • MicroRNAs
  • Patched-1 Receptor
  • Ptch1 protein, mouse
  • Repressor Proteins
  • salvianolic acid B
Topics
  • Animals
  • Benzofurans (pharmacology, therapeutic use)
  • Epigenesis, Genetic
  • Liver Cirrhosis (genetics, metabolism, therapy)
  • Methylation (drug effects)
  • Mice
  • MicroRNAs (genetics, metabolism)
  • Patched-1 Receptor (metabolism)
  • Repressor Proteins (metabolism)

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