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

Abstract

BACKGROUND & AIMS:

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 Wnt5a and its receptor frizzled 2 (Fz2) is elevated during fibrosis progression. 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 fibrosis model 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 injury model), or twice a week for 6 weeks (liver fibrosis model).

RESULTS:

In in vitro studies, Wnt5a enhanced 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 Wnt5a on both HSC proliferation and migration. In in vivo studies, there were no differences in the CCl4 -induced liver injury between KO and WT mice. Hepatic Wnt5a gene expression and plasma Wnt5a levels significantly increased after a single CCl4 injection in both mice. Sfrp5 knockout significantly enhanced CCl4 -induced liver fibrosis.

CONCLUSIONS:

Our findings demonstrate that Sfrp5 may ameliorate mouse liver fibrosis through inhibition of Wnt5a/Fz2 signalling.

• Authors: Norihiro Chatani, Yoshihiro Kamada, Takashi Kizu, Satoshi Ogura, Kunimaro Furuta, Mayumi Egawa, Mina Hamano, Hisao Ezaki, Shinichi Kiso, Akihiko Shimono, Noriyuki Ouchi, Yuichi Yoshida, Tetsuo Takehara
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 35 Issue 8 Pg. 2017-26 (Aug 2015) ISSN: 1478-3231 [Electronic] United States
• PMID: 25488180 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Adaptor Proteins, Signal Transducing
• Intercellular Signaling Peptides and Proteins
• Sfrp5 protein, mouse
• Wnt Proteins
• Wnt-5a Protein
• Wnt5a protein, mouse
• Carbon Tetrachloride

Topics

• Adaptor Proteins, Signal Transducing
• Analysis of Variance
• Animals
• Carbon Tetrachloride (pharmacology)
• Cell Movement (physiology)
• Cell Proliferation (physiology)
• Cells, Cultured
• Disease Models, Animal
• Hepatic Stellate Cells (metabolism)
• Humans
• Intercellular Signaling Peptides and Proteins (metabolism)
• Liver Cirrhosis (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Random Allocation
• Sensitivity and Specificity
• Signal Transduction
• Statistics, Nonparametric
• Wnt Proteins (metabolism)
• Wnt-5a Protein