Acetyl-CoA carboxylase 1 and 2 inhibition ameliorates steatosis and hepatic fibrosis in a MC4R knockout murine model of nonalcoholic steatohepatitis.

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.

• Authors: Mitsuharu Matsumoto, Hiroaki Yashiro, Hitomi Ogino, Kazunobu Aoyama, Tadahiro Nambu, Sayuri Nakamura, Mayumi Nishida, Xiaolun Wang, Derek M Erion, Manami Kaneko
• Journal: PloS one (PLoS One) Vol. 15 Issue 1 Pg. e0228212 ( 2020) ISSN: 1932-6203 [Electronic] United States
• PMID: 31990961 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Isobutyrates
• MC4R protein, mouse
• Oxazoles
• Pyrimidines
• Receptor, Melanocortin, Type 4
• Triglycerides
• Acetyl-CoA Carboxylase
• firsocostat

Topics

• Acetyl-CoA Carboxylase (antagonists & inhibitors)
• Animals
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Gene Knockout Techniques
• Isobutyrates (pharmacology, therapeutic use)
• Liver (drug effects, metabolism, pathology)
• Liver Cirrhosis (drug therapy, metabolism, pathology)
• Mice
• Non-alcoholic Fatty Liver Disease (drug therapy, metabolism, pathology)
• Organ Size (drug effects)
• Oxazoles (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Receptor, Melanocortin, Type 4 (deficiency, genetics)
• Triglycerides (metabolism)