title: 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.
authors.affiliation: Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Fujun
authors.initials: F
authors.lastname: Yu
authors.affiliation: Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Zhongqiu
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Bicheng
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Peihong
authors.initials: P
authors.lastname: Dong
authors.affiliation: Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Jianjian
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology / Q000627:therapeutic use*; D044127:Epigenesis, Genetic; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D008745:Methylation / Q000187:drug effects; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D000072081:Patched-1 Receptor / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D053630:Depsides
chemical_list: D001572:Benzofurans; D035683:MicroRNAs; D000072081:Patched-1 Receptor; D012097:Repressor Proteins; C485852:Dmap1 protein, mouse; C550857:MIRN152 microRNA, mouse; C000606240:Ptch1 protein, mouse; C076944:salvianolic acid B; D053630:Depsides
keywords: DNA methylation; DNA methyltransferase; Patched1; hepatic stellate cells; microRNA-152