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.

Silencing of STE20‐type kinase MST3 in mice with antisense oligonucleotide treatment ameliorates diet‐induced nonalcoholic fatty liver disease

“…Inhibition of ACC activity is expected to reduce intrahepatocellular lipid accumulation since malonyl‐CoA, the enzymatic product of ACC, serves both as the immediate precursor of de novo lipogenesis and as an important allosteric inhibitor of CPT1, the rate‐limiting enzyme for import of acyl‐CoAs into the mitochondria for β‐oxidation 41 . Consistently, ACC blockade has been demonstrated to suppress hepatic steatosis as well as liver inflammation and fibrosis in preclinical models of diet‐ and genetically induced obesity 38,42‐45 . Furthermore, two recently reported prospective clinical trials in NASH patients have revealed that oral treatment with liver‐targeted selective small‐molecule ACC inhibitor GS‐0976 significantly reduces liver steatosis and decreases serum markers of fibrosis 46,47 .…”

“…41 Consistently, ACC blockade has been demonstrated to suppress hepatic steatosis as well as liver inflammation and fibrosis in preclinical models of diet-and genetically induced obesity. 38,[42][43][44][45] Furthermore, two recently reported prospective clinical trials in NASH patients have revealed that oral treatment with liver-targeted selective small-molecule ACC inhibitor GS-0976 significantly reduces liver steatosis and decreases serum markers of fibrosis. 46,47 MK-4074, another liver-specific small-molecule inhibitor of ACC, was also shown to suppress lipogenesis, augment β-oxidation, and lower liver fat content when administered to subjects with hepatic steatosis.…”

Acetyl-CoA carboxylase inhibitors in non-alcoholic steatohepatitis: Is there a benefit?

“…Perhaps the most promising is firsocostat, formerly known as GS-0976. In mice with NASH, this agent improved hepatic steatosis and also reduced hepatic inflammation[ 13 , 14 ]. However, an increase in serum triglyceride, glucose and insulin levels as well in total body fat mass was observed[ 13 , 14 ].…”

“…In mice with NASH, this agent improved hepatic steatosis and also reduced hepatic inflammation[ 13 , 14 ]. However, an increase in serum triglyceride, glucose and insulin levels as well in total body fat mass was observed[ 13 , 14 ]. In another study, a structural analog of GS-0976 reduced hepatic steatosis and hepatic insulin resistance in high-fructose-fed rats[ 15 ].…”

Selective Acetyl-CoA Carboxylase 1 Inhibitor Improves Hepatic Steatosis and Hepatic Fibrosis in a Preclinical Nonalcoholic Steatohepatitis Model

“…Male C57BL/6J mice were purchased from Charles River Laboratories, Japan (Yokohama, Japan) and fed normal chow (CE-2; CLEA Japan, Inc., Tokyo, Japan). Male Mc4r null (MC4R KO) mice were generated following a previous study (Matsumoto et al, 2020). MC4R KO mice and wild-type littermate mice were fed CE-2.…”