Abstract
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, we hypothesize that polyphenol-activated SIRT1 acts upstream of AMPK signaling and hepatocellular lipid metabolism. Here we show that polyphenols, including resveratrol and the synthetic polyphenol S17834, increase SIRT1 deacetylase activity, LKB1 phosphorylation at Ser(428), and AMPK activity. Polyphenols substantially prevent the impairment in phosphorylation of AMPK and its downstream target, ACC (acetyl-CoA carboxylase), elevation in expression of FAS (fatty acid synthase), and lipid accumulation in human HepG2 hepatocytes exposed to high glucose. These effects of polyphenols are largely abolished by pharmacological and genetic inhibition of SIRT1, suggesting that the stimulation of AMPK and lipid-lowering effect of polyphenols depend on SIRT1 activity. Furthermore, adenoviral overexpression of SIRT1 stimulates the basal AMPK signaling in HepG2 cells and in the mouse liver. AMPK activation by SIRT1 also protects against FAS induction and lipid accumulation caused by high glucose. Moreover, LKB1, but not CaMKKbeta, is required for activation of AMPK by polyphenols and SIRT1. These findings suggest that SIRT1 functions as a novel upstream regulator for LKB1/AMPK signaling and plays an essential role in the regulation of hepatocyte lipid metabolism. Targeting SIRT1/LKB1/AMPK signaling by polyphenols may have potential therapeutic implications for dyslipidemia and accelerated atherosclerosis in diabetes and age-related diseases.
Highlights
SIRT1, a mammalian ortholog of Sir2, is an NAD-dependent deacetylase that acts as a master metabolic sensor of NADϩ and modulates cellular metabolism and life span [13,14,15] and delays the onset of agerelated diseases [16]
Because of the associated improvements of hyperlipidemia and atherosclerosis observed in type 1 or type 2 diabetic mice treated with polyphenols [9, 12, 20], these findings suggest that targeting SIRT1/LKB1/AMPK signaling by polyphenols may have potential therapeutic implications for lipid metabolic disorders and accelerated atherosclerosis in diabetes and age-related diseases
The present studies provide the first direct evidence that SIRT1 stimulates AMPK activation via an LKB1-dependent manner and that SIRT1-mediated AMPK activation represents a novel mechanism of the beneficial effects of polyphenols on hepatocyte lipid metabolism
Summary
SIRT1, a mammalian ortholog of Sir (silent information regulator 2), is an NAD-dependent deacetylase that acts as a master metabolic sensor of NADϩ and modulates cellular metabolism and life span [13,14,15] and delays the onset of agerelated diseases [16]. We show here that polyphenols, including resveratrol and 6,8-diallyl-5,7-dihydroxy-2-(2-allyl-3-hydroxy-4-methoxyphenyl)1-H benzo(b)pyran-4-one (S17834), potently increase both SIRT1 deacetylase activity and AMPK activity, which in turn reduces lipid accumulation in HepG2 hepatocytes exposed to high glucose. These responses to polyphenols are dependent on SIRT1. Because of the associated improvements of hyperlipidemia and atherosclerosis observed in type 1 or type 2 diabetic mice treated with polyphenols [9, 12, 20], these findings suggest that targeting SIRT1/LKB1/AMPK signaling by polyphenols may have potential therapeutic implications for lipid metabolic disorders and accelerated atherosclerosis in diabetes and age-related diseases
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