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

التفاصيل البيبلوغرافية
العنوان: Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation
المؤلفون: Swetha Pendem, Igor Mikaelian, Sarani Ghoshal, Anna Zagorska, Archana Vijayakumar, Katie Walker, Bryan C. Fuchs, Robert Brockett, K. Liu, Bruno Marchand, David Lopez, David G. Breckenridge, Li Li, Ricardo Ramirez, Jamie Bates, Saritha Kusam, Dmytro Kornyeyev, Saili Yi, David Newstrom, David Hollenback
المصدر: Journal of Hepatology. 73:896-905
بيانات النشر: Elsevier BV, 2020.
سنة النشر: 2020
مصطلحات موضوعية: Liver Cirrhosis, Male, 0301 basic medicine, Diet, High-Fat, Cell Line, Mice, 03 medical and health sciences, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Fibrosis, Hepatic Stellate Cells, medicine, Animals, Humans, Rats, Wistar, Hepatology, Chemistry, Lipogenesis, Acetyl-CoA carboxylase, medicine.disease, Hepatic stellate cell activation, Rats, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Liver, Lipotoxicity, Hepatic stellate cell, Cancer research, 030211 gastroenterology & hepatology, Steatohepatitis, Hepatic fibrosis, Biomarkers, Acetyl-CoA Carboxylase
الوصف: 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 HSCs, ACC inhibition reduced liver fibrosis in a rat choline-deficient, high-fat diet model and in response to chronic diethylnitrosamine-induced liver injury (in the absence of hepatic lipid accumulation). Conclusions In addition to reducing lipid accumulation in hepatocytes, ACC inhibition also directly impairs the profibrogenic activity of HSCs. Thus, small molecule inhibitors of ACC may lessen fibrosis by reducing lipotoxicity in hepatocytes and by preventing HSC activation, providing a mechanistic rationale for the treatment of patients with advanced liver fibrosis due to NASH. Lay summary Hepatic fibrosis is the most important predictor of liver-related outcomes in patients with non-alcoholic steatohepatitis (NASH). Small molecule inhibitors of acetyl-CoA carboxylase (ACC) reduce hepatic fat content and markers of liver injury in patients with NASH. Herein, we report that inhibition of ACC and de novo lipogenesis also directly suppress the activation of hepatic stellate cells – the primary cell responsible for generating fibrotic scar in the liver – and thus fibrosis. These data provide further evidence for the use of ACC inhibitors to treat patients with NASH and advanced fibrosis.
تدمد: 0168-8278
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d26e3434ea9bae5e5487db79bd3c5389Test
https://doi.org/10.1016/j.jhep.2020.04.037Test
حقوق: OPEN
رقم الانضمام: edsair.doi.dedup.....d26e3434ea9bae5e5487db79bd3c5389
قاعدة البيانات: OpenAIRE