Regulation of AMPK and hepatic metabolism by folic acid supplementation in non-alcoholic fatty liver disease
Sid, V., Wu, N., Sarna, L., Shang, Y., House, J., Siow, Y.L.., and O, K. (2016) Regulation of AMPK and hepatic metabolism by folic acid supplementation in non-alcoholic fatty liver disease. Experimental Biology 2016, April 2-6, 2016 San Diego, USA, FASEB J. 30(1 Suppl): 870.3
Non-alcoholic fatty liver disease (NAFLD) is a worldwide epidemic associated with obesity and type 2 diabetes. Chronic high-fat diet consumption promotes NAFLD which is characterized by hepatic lipid accumulation, hyperglycemia and hyperlipidemia. Emerging evidence suggests that metabolic aberration during NAFLD may be related to dysregulation of AMP-activated protein kinase (AMPK). AMPK is an endogenous energy sensor involved in regulating lipid and glucose metabolism, which has been proposed as a potential therapeutic target in NAFLD and its associated metabolic disorders. Folic acid is an essential B vitamin that has been implicated in NAFLD through improvement of liver function. The aim of our study was to investigate the mechanisms by which folic acid supplementation regulated hepatic AMPK and its impact on cholesterol and glucose metabolism. Male C57BL/6J mice were fed a control diet (10% kcals fat), a high-fat diet (60% kcals fat) or a high-fat diet supplemented with folic acid for 5 weeks. Mice fed a high-fat diet exhibited fatty liver, hyperglycemia, elevated activity of hepatic HMG-CoA reductase and lower AMPK activity. Folic acid supplementation restored AMPK activity, attenuated hepatic lipid accumulation and reduced blood glucose levels. Activation of AMPK by folic acid was mediated, in part, through activation of its upstream kinase LKB1. Folic acid-induced AMPK activation could attenuate HMG-CoA reductase activity via AMPK-dependent phosphorylation of the reductase and hence reduce hepatic cholesterol biosynthesis. Our results suggest that folic acid supplementation can improve cholesterol and glucose metabolism through restoration of AMPK activation in the liver, which may have a therapeutic implication in mitigating hepatic lipid accumulation and hyperglycemia in NAFLD.
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