Acetyl-CoA carboxylase (ACC) 1 and ACC2 are essential rate-limiting
enzymes that synthesize
malonyl-CoA (M-
CoA) from
acetyl-CoA. ACC1 is predominantly expressed in lipogenic tissues and regulates the de novo lipogenesis flux. It is upregulated in the liver of patients with
nonalcoholic fatty liver disease (
NAFLD), which ultimately leads to the formation of
fatty liver. Therefore, selective ACC1 inhibitors may prevent the pathophysiology of
NAFLD and
nonalcoholic steatohepatitis (NASH) by reducing hepatic fat,
inflammation, and
fibrosis. Many studies have suggested ACC1/2 dual inhibitors for treating
NAFLD/NASH; however, reports on selective ACC1 inhibitors are lacking. In this study, we investigated the effects of compound-1, a selective ACC1 inhibitor for treating
NAFLD/NASH, using preclinical in vitro and in vivo models. Compound-1 reduced M-
CoA content and inhibited the incorporation of [14C]
acetate into
fatty acids in HepG2 cells. Additionally, it reduced hepatic M-
CoA content and inhibited de novo lipogenesis in C57BL/6J mice after a single dose. Furthermore, compound-1 treatment of 8 weeks in Western diet-fed
melanocortin 4 receptor knockout mice-
NAFLD/NASH mouse model-improved liver
hypertrophy and reduced hepatic
triglyceride content. The reduction of hepatic M-
CoA by the selective ACC1 inhibitor was highly correlated with the reduction in hepatic steatosis and
fibrosis. These findings support further investigations of the use of this ACC1 inhibitor as a new treatment of NFLD/NASH. SIGNIFICANCE STATEMENT: This is the first study to demonstrate that a novel selective inhibitor of
acetyl-CoA carboxylase (ACC) 1 has anti-
nonalcoholic fatty liver disease (
NAFLD) and anti-
nonalcoholic steatohepatitis (NASH) effects in preclinical models. Treatment with this compound significantly improved hepatic steatosis and
fibrosis in a mouse model. These findings support the use of this ACC1 inhibitor as a new treatment for
NAFLD/NASH.