Secreted frizzled‐related protein 5 (Sfrp5) decreases hepatic stellate cell activation and liver fibrosis. (20th January 2015)

• Record Type: Journal Article
• Authors: Chatani, Norihiro; Kamada, Yoshihiro; Kizu, Takashi; Ogura, Satoshi; Furuta, Kunimaro; Egawa, Mayumi; Hamano, Mina; Ezaki, Hisao; Kiso, Shinichi; Shimono, Akihiko; Ouchi, Noriyuki; Yoshida, Yuichi; Takehara, Tetsuo
• Is Part Of: Liver international. Volume 35:Number 8(2015:Aug.)
• Page Start: 2017
• Page End: 2026
• Publication Date: 2015-01-20
• Subjects: Liver -- Periodicals; Liver -- Diseases -- Periodicals; 616.362
• DOI: 10.1111/liv.12757
• Languages: English
• ISSNs: 1478-3223

Abstract

<abstract abstract-type="main" id="liv12757-abs-0001"> <title>Abstract</title> <sec id="liv12757-sec-0001" sec-type="section"> <title>Background & Aims</title> <p>Obesity‐related adipocytokine dysregulation is known to accelerate liver fibrosis progression. Recently, a natural Wnt5a inhibitor, secreted frizzled‐related protein 5 (Sfrp5), was identified as a novel adipocytokine that has reduced expression in obese adipose tissue in both rodents and human. In addition, hepatic gene expression of <italic>Wnt5a</italic> and its receptor frizzled 2 (<italic>Fz2</italic>) is elevated during fibrosis progression. Therefore, Sfrp5 could have biological significance in liver fibrosis.</p> </sec> <sec id="liv12757-sec-0002" sec-type="section"> <title>Methods</title> <p>We first investigated the effects of Sfrp5 on primary cultured mouse hepatic stellate cells (HSCs) <italic>in vitro</italic>. Next, to elucidate the roles of Sfrp5 in liver fibrosis, we investigated a carbon‐tetrachloride (CCl<sub>4</sub>)‐induced liver fibrosis model using <italic>Sfrp5</italic> knockout (KO) and wild type (WT) mice <italic>in vivo</italic>. Each mouse was injected intraperitoneally with CCl<sub>4</sub> (0.5 ml/kg) or olive oil as a single dose (acute liver injury model), or twice a week for 6 weeks (liver fibrosis model).</p> </sec> <sec id="liv12757-sec-0003" sec-type="section"> <title>Results</title> <p>In <italic>in vitro</italic> studies, Wnt5a enhanced both proliferation and migration of HSCs, and these effects could be completely blocked by Sfrp5. Moreover, siRNA knockdown of <italic>Fz2</italic> in HSCs could block the effects of Wnt5a on both HSC proliferation and migration. In <italic>in vivo</italic> studies, there were no differences in the CCl<sub>4</sub>‐induced liver injury between KO and WT mice. Hepatic <italic>Wnt5a</italic> gene expression and plasma Wnt5a levels significantly increased after a single CCl<sub>4</sub> injection in both mice. <italic>Sfrp5</italic> knockout significantly enhanced CCl<sub>4</sub>‐induced liver fibrosis.</p> </sec> <sec id="liv12757-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Our findings demonstrate that Sfrp5 may ameliorate mouse liver fibrosis through inhibition of Wnt5a/Fz2 signalling.</p> </sec> </abstract>