Secreted frizzled-related protein 5 (Sfrp5) decreases hepatic stellate cell activation and liver fibrosis

Background & Aims Obesity-related adipocytokine dysregulation is known to accelerate liver fibrosisprogression. Recently, a natural Wnt5ainhibitor, 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 Wnt5aand its receptor frizzled2 (Fz2) is elevated during fibrosisprogression. Therefore, Sfrp5 could have biological significance in liver fibrosis. Methods We first investigated the effects of Sfrp5 on primary cultured mouse hepatic stellate cells(HSCs) in vitro. Next, to elucidate the roles of Sfrp5 in liver fibrosis, we investigated a carbon-tetrachloride ( CCl4)-induced liver fibrosismodel using Sfrp5 knockout (KO) and wild type (WT) mice in vivo. Each mouse was injected intraperitoneally with CCl4(0.5 ml/kg) or olive oil as a single dose (acute liver injurymodel), or twice a week for 6 weeks (liver fibrosismodel). Results In in vitro studies, Wnt5aenhanced both proliferation and migration of HSCs, and these effects could be completely blocked by Sfrp5. Moreover, siRNA knockdown of Fz2 in HSCs could block the effects of Wnt5aon both HSC proliferation and migration. In in vivo studies, there were no differences in the CCl4-induced liver injurybetween KO and WT mice. Hepatic Wnt5agene expression and plasma Wnt5alevels significantly increased after a single CCl4injection in both mice. Sfrp5 knockout significantly enhanced CCl4-induced liver fibrosis. Conclusions Our findings demonstrate that Sfrp5 may ameliorate mouse liver fibrosisthrough inhibition of Wnt5a/Fz2 signalling.