Hic-5 deficiency attenuates the activation of hepatic stellate cells and liver fibrosis through upregulation of Smad7 in mice
Hic-5 deficiency attenuates the activation of hepatic stellate cells and liver fibrosis through upregulation of Smad7 in mice
复制标题
Hic-5 缺陷通过上调小鼠中的 Smad7 减弱肝星状细胞的活化和肝纤维化
DOI：
10.1016/j.jhep.2015.08.026
复制
发表时间：
2016-01-01
影响因子：
25.7
通讯作者：
Miyazaki, Akira
中科院分区：
文献类型：
--
作者：
Lei, Xiao-Feng;Fu, Wenguang;Miyazaki, Akira
背景与目的：过氧化氢诱导克隆5（Hic-5），也称为转化生长因子β-1诱导转录1蛋白（Tgfb1i1），被发现由TGF-β诱导。先前的研究表明，TGF-β 是肝纤维化过程中肝星状细胞 (HSC) 激活的主要介质。然而，这个过程仍然难以捉摸。在本研究中，我们旨在明确 Hic-5 在 HSC 激活和肝纤维化中的作用。方法：我们通过实时定量逆转录酶聚合酶链反应、Western blot 和免疫组织化学检测 Hic-5 在 HSC 激活过程中以及纤维化肝组织中的表达水平。对Hic-5敲除（KO）和野生型（WT）小鼠进行胆管结扎（BDL）或注射四氯化碳（CCl4）诱导肝纤维化。结果：在人纤维化肝组织的活化HSC以及BDL或CCl4诱导的小鼠肝纤维化中，Hic-5表达强烈上调。 Hic-5 缺陷显着减弱小鼠肝纤维化和 HSC 活化。此外，体内 siRNA 敲低 Hic-5 可抑制 CCl4 诱导的小鼠肝纤维化。从机制上讲，Hic-5的缺乏显着抑制了TGF-β/Smad2信号通路，这通过增加Smad7的表达来证明，导致活化的HSC中胶原蛋白的产生和α-平滑肌肌动蛋白的表达减少。结论：Hic-5的缺乏通过上调Smad7来减少TGF-β/Smad2信号传导，从而减弱HSC的活化和肝纤维化。因此，Hic-5可以被视为肝纤维化的潜在治疗靶点。 (C) 2015 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
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.