Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation

作者：Jamie Bates, Archana Vijayakumar, Sarani Ghoshal, Bruno Marchand, Saili Yi, Dmytro Kornyeyev, Anna Zagórska, David Hollenback, Katie S. Walker, Kathy Liu, Swetha Pendem, David W. Newstrom, Robert Brockett, Igor Mikaelian, Saritha Kusam, Ricardo Ramírez, David López, Li Li, Bryan C. Fuchs, David G. Breckenridge · 发表于：Journal of Hepatology · 年份：2020 · DOI：10.1016/j.jhep.2020.04.037 · 被引用次数：229 · 研究领域：Liver Disease Diagnosis and Treatment、Liver physiology and pathology、Alcohol Consumption and Health Effects

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by hepatic lipid accumulation, inflammation, and progressive fibrosis. Acetyl-CoA carboxylase (ACC) catalyzes the rate-limiting step of de novo lipogenesis and regulates fatty acid β-oxidation in hepatocytes. ACC inhibition reduces hepatic fat content and markers of liver injury in patients with NASH; however, the effect of ACC inhibition on liver fibrosis has not been reported. METHODS: A direct role for ACC in fibrosis was evaluated by measuring de novo lipogenesis, procollagen production, gene expression, glycolysis, and mitochondrial respiration in hepatic stellate cells (HSCs) in the absence or presence of small molecule inhibitors of ACC. ACC inhibitors were evaluated in rodent models of liver fibrosis induced by diet or the hepatotoxin, diethylnitrosamine. Fibrosis and hepatic steatosis were evaluated by histological and biochemical assessments. RESULTS: Inhibition of ACC reduced the activation of TGF-β-stimulated HSCs, as measured by both α-SMA expression and collagen production. ACC inhibition prevented a metabolic switch necessary for induction of glycolysis and oxidative phosphorylation during HSC activation. While the molecular mechanism by which inhibition of de novo lipogenesis blocks glycolysis and oxidative phosphorylation is unknown, we definitively show that HSCs require de novo lipogenesis for activation. Consistent with this direct antifibrotic mechanism in HSC...