Abstract
Non-alcoholic steatohepatitis (NASH) is characterized by inflammation and fibrosis, in addition to steatosis, of the liver, but no therapeutic agents have yet been established. The mast cell protease chymase can generate angiotensin II, matrix metalloproteinase-9 and transforming growth factor-β, all of which are associated with liver inflammation or fibrosis. In animal models of NASH, augmented chymase has been observed in the liver. In histological analysis, chymase inhibitor prevented hepatic steatosis, inflammation, and fibrosis. Chymase inhibitor also attenuated the augmentation of angiotensin II, matrix metalloproteinase-9, and transforming growth factor-β observed in the liver of NASH. Oxidative stress, inflammatory markers, and collagen were attenuated by chymase inhibition. Moreover, chymase inhibitor showed a mitigating effect on established NASH, and survival rates were significantly increased by treatment with chymase inhibitor. In this review, we propose that chymase inhibitor has potential as a novel therapy for NASH.
Highlights
Non-alcoholic fatty liver disease (NAFLD) has been recognized as the most common form of liver disease (Angulo, 2002; Clark et al, 2002)
The inhibition of chymase using low molecule inhibitors resulted in a significant reduction of inflammation, steatosis, and fibrosis in rat and hamster Non-alcoholic steatohepatitis (NASH) models (Tashiro et al, 2010; Masubuchi et al, 2013; Miyaoka et al, 2017). These findings indicate that chymase may be involved in inflammation, steatosis, and fibrosis during the development and progression of NASH (Figure 1)
A low molecule chymase inhibitor significantly attenuated chymase activity and decreased angiotensin II, matrix metalloproteinase (MMP)-9 and collagen I levels in the liver in an methionine- and choline-deficient (MCD) diet-fed NASH hamster model, when administration of the inhibitor was initiated at the same time as the MCD diet (Tashiro et al, 2010; Masubuchi et al, 2013)
Summary
Non-alcoholic fatty liver disease (NAFLD) has been recognized as the most common form of liver disease (Angulo, 2002; Clark et al, 2002). NAFLD and NASH are associated with metabolic syndrome resulting from obesity, insulin resistance, hyperlipidemia, and hypertension. The inhibition of chymase using low molecule inhibitors resulted in a significant reduction of inflammation, steatosis, and fibrosis in rat and hamster NASH models (Tashiro et al, 2010; Masubuchi et al, 2013; Miyaoka et al, 2017). These findings indicate that chymase may be involved in inflammation, steatosis, and fibrosis during the development and progression of NASH (Figure 1)
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