Abstract
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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is a liver disease characterized by excessive fat accumulation in hepatocytes that is not caused by alcohol consumption (Friedman et al, 2018; Vernon et al, 2011)
We investigated the effects of compound-1 on hepatic steatosis and fibrosis by using western diet (WD)-fed melanocortin 4 receptor (MC4R) KO mice, a genetic and obesogenic dietary model that mimics the human pathophysiology of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) with obesity, insulin resistance, and excessive lipid accumulation, as well as enhanced liver fibrosis (Itoh et al, 2011; Konuma et al, 2015; Shiba et al, 2018)
Compound-2 inhibited mouse acetyl-CoA carboxylase 1 (ACC1) and ACC2 with IC50 values of 6.0 nM and 6.4 nM, respectively. These results indicate that compound-1 is selective for ACC1 inhibition, whereas compound-2 inhibits both ACC1 and ACC2
Summary
Nonalcoholic fatty liver disease (NAFLD) is a liver disease characterized by excessive fat accumulation in hepatocytes that is not caused by alcohol consumption (Friedman et al, 2018; Vernon et al, 2011). Nonalcoholic steatohepatitis (NASH) is a sub-category of NAFLD and is defined on the basis of the following liver biopsy histological features: lobular inflammation, hepatocellular ballooning, fibrosis, and steatosis (Williams et al, 2011; Siddiqui et al, 2018). Hepatic steatosis is caused by an imbalance in hepatic lipid metabolism favoring the storage of lipids within the liver (Cohen et al, 2011), which triggers hepatic inflammation and, subsequently, fibrosis, which drives NASH progression. Metabolic syndromes, such as obesity, insulin resistance, and dyslipidemia, represent the major risk factors for the development of NAFLD/NASH. Multiple clinical trials are focusing on correcting the dysfunctional lipid metabolism via the application of lipid metabolism pathway modulators, nuclear hormone receptor agonists, and glycemic modulators (Esler and Bence, 2019)
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