Abstract
Acetyl-CoA carboxylase (ACC) catalyzes the rate-limiting step in de novo lipogenesis, which is increased in the livers of patients with nonalcoholic steatohepatitis. GS-0976 (firsocostat), an inhibitor of isoforms ACC1 and ACC2, reduced hepatic steatosis and serum fibrosis biomarkers such as tissue inhibitor of metalloproteinase 1 in patients with nonalcoholic steatohepatitis in a randomized controlled trial, although the impact of this improvement on fibrosis has not fully been evaluated in preclinical models. Here, we used Western diet-fed melanocortin 4 receptor-deficient mice that have similar phenotypes to nonalcoholic steatohepatitis patients including progressively developed hepatic steatosis as well as fibrosis. We evaluated the effects of ACC1/2 inhibition on hepatic fibrosis. After the confirmation of significant hepatic fibrosis with a 13-week pre-feeding, GS-0976 (4 and 16 mg/kg/day) treatment for 9 weeks lowered malonyl-CoA and triglyceride content in the liver and improved steatosis, histologically. Furthermore, GS-0976 reduced the histological area of hepatic fibrosis, hydroxyproline content, mRNA expression level of type I collagen in the liver, and plasma tissue metalloproteinase inhibitor 1, suggesting an improvement of hepatic fibrosis. The treatment with GS-0976 was also accompanied by reductions of plasma ALT and AST levels. These data demonstrate that improvement of hepatic lipid metabolism by ACC1/2 inhibition could be a new option to suppress fibrosis progression as well as to improve hepatic steatosis in nonalcoholic steatohepatitis.
Highlights
The prevalence of nonalcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide and the most common liver disorder in the western world [1]
Our study demonstrated that Western diet (WD)-fed melanocortin 4 receptor (MC4R) KO mice had many characteristics in common with nonalcoholic steatohepatitis (NASH) patients, such as hepatic steatosis, increased Sirius Red-positive area, hepatic hydroxyproline content, fibrosis-related gene expression in the liver and plasma liver enzyme levels as reported previously [29, 30]
It is known that ACC1/2 dual inhibition reduces hepatic triglyceride content both in normal rodents [20, 24] and in rats with diet-induced obesity [25]
Summary
The prevalence of nonalcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide and the most common liver disorder in the western world [1]. GS-0976 (firsocostat), a liver-targeted potent inhibitor of both ACC1/2, has been reported to inhibit human ACC1 and ACC2 with IC50 values of 2.1 and 6.1 nM, respectively [25] This compound has been shown to reduce DNL in cultured HepG2 cells, stimulate fatty acid oxidation in cultured C2C12 cells, and reduce hepatic DNL in normal rats [25, 26]. In the same study, GS-0976 did not significantly decrease levels of two other serum fibrosis markers, Acetyl-CoA carboxylase inhibition and nonalcoholic steatohepatitis procollagen III N-terminal peptide and hyaluronic acid It has not been verified whether inhibition of ACC1/2 would improve hepatic fibrosis in NASH. Because ACC inhibition has been reported to reduce hepatic steatosis but elevate plasma triglyceride concentrations in mice, rats and patients with NASH [20, 31], we monitored its influence on plasma parameters to investigate the usefulness of ACC dual inhibition
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