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J Hepatol. 2016 Jan;64(1):110-7. doi: 10.1016/j.jhep.2015.08.026. Epub 2015 Aug 31.

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

Author information

1
Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan.
2
Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Sichuan Medical University, Luzhou, China.
3
Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan. Electronic address: shuri@pharm.showa-u.ac.jp.
4
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Sichuan Medical University, Luzhou, China.

Abstract

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-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.

KEYWORDS:

Hepatic stellate cells; Hic-5; Liver fibrosis; Smad2; Smad7; Tgfb1i1

PMID:
26334580
DOI:
10.1016/j.jhep.2015.08.026
[Indexed for MEDLINE]

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