期刊
JOURNAL OF HEPATOLOGY
卷 64, 期 1, 页码 110-117出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2015.08.026
关键词
Hic-5; Tgfb1i1; Smad2; Smad7; Hepatic stellate cells; Liver fibrosis
资金
- Japan Society for the Promotion of Science [26860588, 26461149, 26461368]
- Showa University Medical Foundation
- Takeda Science Foundation
- Natural Science Foundation of China [81400657]
- MEXT (Ministry of Education, Culture, Sports, Science and Technology)
- Grants-in-Aid for Scientific Research [15K09418, 26461149, 26860588, 26461368] Funding Source: KAKEN
Background & Aim: Hydrogen peroxide-inducible clone-5 (Hic-5), also named as transforming growth factor beta-1-induced transcript 1 protein (Tgfb1i1), was found to be induced by TGF-beta. Previous studies have shown that TGF-beta is a principal mediator of hepatic stellate cell (HSC) activation in liver fibrosis. However, this process remains elusive. In this study, we aimed to define the role of Hic-5 in HSC activation and liver fibrosis. Methods: We examined the expression levels of Hic-5 during HSCs activation and in fibrotic liver tissues by quantitative real-time reverse transcriptase polymerase chain reaction, Western blot and immunohistochemistry. Hic-5 knockout (KO) and wild-type (WT) mice were subjected to bile duct ligation (BDL) or carbon tetrachloride (CCl4) injection to induce liver fibrosis. Results: Hic-5 expression was strongly upregulated in activated HSCs of the human fibrotic liver tissue and BDL or CCl4-induced mouse liver fibrosis. Hic-5 deficiency significantly attenuated mouse liver fibrosis and HSC activation. Furthermore, Hic-5 knockdown by siRNA in vivo repressed CCl4-induced liver fibrosis in mice. Mechanistically, the absence of Hic-5 significantly inhibited the TGF-beta/Smad2 signaling pathway, proved by increasing Smad7 expression, resulting in reduced collagen production and alpha-smooth muscle actin expression in the activated HSCs. Conclusion: Hic-5 deficiency attenuates the activation of HSCs and liver fibrosis though reducing the TGF-beta/Smad2 signaling by upregulation of Smad7. Thus, Hic-5 can be regarded as a potential therapeutic target for liver fibrosis. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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