Repression of Smad7 mediated by DNMT1 determines hepatic stellate cell activation and liver fibrosis in rats

被引：79
作者：
Bian, Er-Bao [1 ,2 ]
Huang, Cheng [1 ,2 ]
Wang, Hua [1 ,2 ]
Chen, Xiao-Xia [1 ,2 ]
Zhang, Lei [2 ]
Lv, Xiong-Wen [2 ]
Li, Jun [1 ,2 ]
机构：
[1] Anhui Med Univ, Inst Liver Dis, Hefei 230032, Anhui, Peoples R China
[2] Anhui Med Univ, Sch Pharm, Hefei 230032, Anhui, Peoples R China
来源：
TOXICOLOGY LETTERS | 2014年 / 224卷 / 02期
基金：
美国国家科学基金会;
关键词：
Liver fibrosis; Hepatic stellate cell (HSC); DNA methylation; DNA methyltransferase 1 (DNMT1); Smad7; MULTIPLE CPG ISLANDS; GROWTH-FACTOR-BETA; TGF-BETA; DNA METHYLTRANSFERASE-1; PROTEIN EXPRESSION; FIBROGENESIS; HYPERMETHYLATION; METHYLATION; CANCER; DIFFERENTIATION;
D O I：
10.1016/j.toxlet.2013.10.038
中图分类号：
R99 [毒物学（毒理学）];
学科分类号：
100405 ;
摘要：
Conversion of hepatic stellate cells (HSCs) into hepatic myofibroblasts is a necessary event during the development of liver fibrosis. DNA methyltransferase 1 (DNMT1), which catalyzes DNA methylation and subsequently leads to the transcriptional repression of profibrotic genes, is selectively induced in myofibroblasts from diseased livers. Treatment of HSC with the DNA methylation inhibitor, 5-aza-2'-deoxycytidine (5-azadC), prevented TGF-beta 1-induced proliferation and alpha-smooth muscle actin (alpha-SMA) and collagen expression. 5-AzadC also rescued TGF-beta 1-induced suppression of Smad7 expression which occurs during HSC activation. Similarly, silencing the expression of the DNMT1 gene ameliorated the suppression of Smad7 expression by TGF-beta 1. In addition, DNMT1 inhibition, by 5-azadC or DNMT1 silencing, prevented the phosphorylation of Smad2 and Smad3. These studies suggest that epigenetic repression of Smad7 promotes the phosphorylation of Smad2 and Smad3 that may be an important molecular mechanism for perpetuated HSC activation and liver fibrosis. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码：175 / 185
页数：11
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