title: Chymase inhibitor ameliorates hepatic steatosis and fibrosis on established non-alcoholic steatohepatitis in hamsters fed a methionine- and choline-deficient diet.
abstract: OBJECTIVE
  Chymase plays a role in the augmentation of angiotensin II formation, which is involved in liver fibrosis. The therapeutic effects of a chymase inhibitor, TY-51469, on established hepatic steatosis and fibrosis were investigated in a model of developed non-alcoholic steatohepatitis.
  
  
  METHODS
  Hamsters were fed a normal diet or methionine- and choline-deficient (MCD) diet for 12 weeks. Then, treatment with TY-51469 (1 mg/kg per day) or placebo was initiated, and the treatment was continued concurrently with the MCD diet for an additional 12 weeks.
  
  
  RESULTS
  At 12 weeks after initiating the MCD diet, marked hepatic steatosis and fibrosis were observed in MCD diet-fed hamsters. Malondialdehyde and gene expression levels of collagen I, collagen III, α-smooth muscle actin (α-SMA) and Rac-1 in liver extracts were also increased in the MCD-diet-fed hamsters at 12 weeks. At 24 weeks, hepatic steatosis and fibrosis were more prominent in the placebo-treated hamsters that were fed the MCD-diet for 24 weeks versus 12 weeks. Hamsters treated with TY-51469 for 12 weeks after being on a 12-week MCD diet had significant ameliorations in both hepatic steatosis and fibrosis, and there were no significant differences compared to normal diet-fed hamsters. There were significant augmentations in angiotensin II and malondialdehyde, and gene expressions of collagen I, collagen III, α-SMA and Rac-1 in the placebo-treated hamsters at 24 weeks; however, these levels were reduced to normal levels in the TY-51469-treated hamsters.
  
  
  CONCLUSIONS
  TY-51469 not only prevented the progression of hepatic steatosis and fibrosis, but also ameliorated hepatic steatosis and fibrosis.
authors.affiliation: Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Masubuchi
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Denan
authors.initials: D
authors.lastname: Jin
authors.forename: Keitaro
authors.initials: K
authors.lastname: Tashiro
authors.forename: Koji
authors.initials: K
authors.lastname: Komeda
authors.forename: Zhong-Lian
authors.initials: ZL
authors.lastname: Li
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Otsuki
authors.forename: Haruki
authors.initials: H
authors.lastname: Okamura
authors.forename: Michihiro
authors.initials: M
authors.lastname: Hayashi
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Uchiyama
keywords: angiotensin II; chymase; fibrosis; non-alcoholic steatohepatitis; steatosis