title: Secreted frizzled-related protein 5 (Sfrp5) decreases hepatic stellate cell activation and liver fibrosis.
abstract: OBJECTIVE
  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.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Chatani
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.|Department of Molecular Biochemistry & Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kamada
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kizu
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogura
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Kunimaro
authors.initials: K
authors.lastname: Furuta
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Egawa
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Mina
authors.initials: M
authors.lastname: Hamano
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Ezaki
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kiso
authors.affiliation: TransGenic Inc, Kobe, Hyogo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Shimono
authors.affiliation: Department of Molecular Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ouchi
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000704:Analysis of Variance; D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011897:Random Allocation; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002251:Carbon Tetrachloride; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C487972:Sfrp5 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C438615:Wnt5a protein, mouse
keywords: JNK; Sfrp5; Wnt5a; hepatic stellate cell; liver fibrosis