Chymase inhibitor prevents the nonalcoholic steatohepatitis in hamsters fed a methionine- and choline-deficient diet.
OBJECTIVE
Mast cells may be involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). The mast cell protease chymase contributes to the formation of angiotensin II and matrix metalloproteinase (MMP)-9, both of which are intimately involved in liver fibrosis. Therefore, we hypothesized that chymase plays an important role in the development of NASH.


METHODS
Hamsters were fed a methionine- and choline-deficient (MCD) diet for 8 weeks. These animals were divided into two groups and received either TY-51469 (1 mg/kg per day) or placebo. A third group was fed a normal diet as a control.


RESULTS
Total plasma bilirubin, triglycerides, and hyaluronic acid levels were significantly higher in the MCD diet-fed hamsters than in the normal diet-fed hamsters, but the levels were significantly lower in chymase inhibitor-treated MCD diet-fed hamsters than in placebo-treated MCD diet-fed hamsters. Using histological analysis, marked steatosis and fibrosis were observed in MCD diet-fed hamsters, but these changes were significantly attenuated by treatment with the chymase inhibitor. Increases in mast cells and chymase-positive cells were observed in the liver after the MCD diet, but the increases disappeared in the chymase inhibitor-treated group. The significant increase observed in chymase activity in liver tissue extract from the MCD diet-fed group was also reduced by treatment with the chymase inhibitor. Chymase inhibition significantly reduced not only angiotensin II expression but also matrix metallopeptidase 9 activity in MCD diet-fed hamsters.


CONCLUSIONS
These findings demonstrate that the mast cell protease chymase may play a crucial role in the development of NASH in hamsters.
Tashiro
Keitaro
K
Department of Pharmacology, Osaka Medical College, Daigaku-machi, Takatsuki, Japan.
Takai
Shinji
S
Jin
Denan
D
Yamamoto
Hiromi
H
Komeda
Koji
K
Hayashi
Michihiro
M
Tanaka
Kazuhiko
K
Tanigawa
Nobuhiko
N
Miyazaki
Mizuo
M