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


CONCLUSIONS
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.
Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan.
Xiao-Feng
XF
Lei
Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Sichuan Medical University, Luzhou, China.
Wenguang
W
Fu
Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan. Electronic address: shuri@pharm.showa-u.ac.jp.
Joo-Ri
JR
Kim-Kaneyama
Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan.
Tomokatsu
T
Omoto
Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan.
Takuro
T
Miyazaki
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Sichuan Medical University, Luzhou, China.
Bo
B
Li
Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan.
Akira
A
Miyazaki
D000199:Actins / Q000032:analysis; D000818:Animals; D002251:Carbon Tetrachloride; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000172:deficiency*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000172:deficiency*; D055166:Hepatic Stellate Cells / Q000502:physiology*; D006801:Humans; D060588:LIM Domain Proteins / Q000032:analysis / Q000172:deficiency*; D008103:Liver Cirrhosis / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051899:Smad2 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D015854:Up-Regulation
D000199:Actins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C090090:Tgfb1i1 protein, mouse; D016212:Transforming Growth Factor beta; C544013:alpha-smooth muscle actin, mouse; D002251:Carbon Tetrachloride
Hepatic stellate cells; Hic-5; Liver fibrosis; Smad2; Smad7; Tgfb1i1