Hic-5 deficiency attenuates the activation of hepatic stellate cells and liver fibrosis through upregulation of Smad7 in mice

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• 作者：Xiao-Feng Lei¹ ; ^&dagger ; ; Wenguang Fu¹ ; ² ; ^&dagger ; ; Joo-ri Kim-Kaneyama¹ ; ^{shuri@pharm.showa-u.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Tomokatsu Omoto¹ ; Takuro Miyazaki¹ ; Bo Li² ; Akira Miyazaki¹
• 关键词：Ad-Hic-5/flag ; adenovirus-mediated flag-tagged Hic-5 ; Ad-β-gal ; adenovirus-mediated β-galactosidase ; α-SMA ; alpha smooth muscle actin ; BDL ; bile duct ligation ; CCl4 ; carbon tetrachloride ; COL ; collagen ; ECM ; extracellular matrix ; GAPDH ; glyceraldehyde 3-phosphate dehydrogenase ; Hep ; hepatocytes ; Hic-5 ; Hydrogen peroxide-inducible clone-5 ; Hic-5 KO ; Hic-5 knockout ; HSCs ; hepatic stellate cells ; LSECs ; liver sinusoid endothelial cells ; P-Smad2 ; phosphorylated Smad2 ; siRNA ; small interfering RNA ; T
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：64
• 期：1
• 页码：110-117
• 全文大小：2961 K

文摘

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-β. Previous studies have shown that TGF-β 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-β/Smad2 signaling pathway, proved by increasing Smad7 expression, resulting in reduced collagen production and α-smooth muscle actin expression in the activated HSCs.

Conclusion

Hic-5 deficiency attenuates the activation of HSCs and liver fibrosis though reducing the TGF-β/Smad2 signaling by upregulation of Smad7. Thus, Hic-5 can be regarded as a potential therapeutic target for liver fibrosis.