SIRT1 Regulates Hepatocyte Lipid Metabolism through Activating AMP-activated Protein Kinase *

摘要: Resveratrol may protect against metabolic disease through activating SIRT1 deacetylase. Because we have recently defined AMPK activation as a key mechanism for the beneficial effects of polyphenols on hepatic lipid accumulation, hyperlipidemia, and atherosclerosis in type 1 diabetic mice, hypothesize that polyphenol-activated acts upstream signaling hepatocellular metabolism. Here show polyphenols, including resveratrol synthetic polyphenol S17834, increase deacetylase activity, LKB1 phosphorylation at Ser428, activity. Polyphenols substantially prevent impairment its downstream target, ACC (acetyl-CoA carboxylase), elevation expression FAS (fatty acid synthase), accumulation human HepG2 hepatocytes exposed to high glucose. These are largely abolished by pharmacological genetic inhibition SIRT1, suggesting stimulation lipid-lowering effect depend Furthermore, adenoviral overexpression stimulates basal cells mouse liver. also protects induction caused Moreover, LKB1, but not CaMKKβ, is required SIRT1. findings suggest functions novel regulator LKB1/AMPK plays an essential role regulation hepatocyte Targeting SIRT1/LKB1/AMPK potential therapeutic implications dyslipidemia accelerated diabetes age-related diseases.