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

By X. Hou, Shanqin Xu, Karlene A. Maitland-Toolan, Kaori Sato, B. Jiang, Y. Ido, Fan Lan, K. Walsh, M. Wierzbicki, T. Verbeuren and 2 more. Journal of Biological Chemistry, 2008

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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 Ser428, 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 CaMKKβ, 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.

Subfields: Epidemiology, Geriatrics and Gerontology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9e49e0b1cdd5aa9b2011aa64933e83b37f7793b6

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Citations in the corpus

Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. (2008, background): “It is possible that the recently described SIRT1-dependent regulation of LKB1 plays a role in this regulation (Hou et al., 2008).”
SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function (2012, background): “Alternatively, resveratrol may first activate SIRT1 in vivo, leading to AMPK activation via deacetylation and activation of the AMPK kinase LKB1 (Hou et al., 2008; Ivanov et al., 2008; Lan et al., 2008).”
Sirt1 and the Mitochondria (2016, background): “That Sirt1 may act upstream of AMPK has support in a previous report, which showed that Sirt1 could potentially deacetylate and activate the major AMPK activating kinase, Serine/threonine kinase 11 (STK11) (or liver kinase B1, LKB1) (Lan et al., 2008).”
SIRTUIN 1 AND SIRTUIN 3: PHYSIOLOGICAL MODULATORS OF METABOLISM (2012, background): “On the other hand, SIRT1 regulates LKB1, an upstream regulator of AMPK (140, 386).”
AMPK Phosphorylates and Inhibits SREBP Activity to Attenuate Hepatic Steatosis and Atherosclerosis in Diet-induced Insulin Resistant Mice (2011, neutral): “It is likely that other nutrient sensors controlled by AMPK, such as downstream kinases like mTORC1, or concurrent regulation of SIRT1 and AMPK (Hou et al., 2008), may also modulate SREBP-dependent lipid synthesis in type 2 diabetes.”
AMPK: an emerging drug target for diabetes and the metabolic syndrome. (2009, background): “In parallel, SIRT1 activation by resveratrol and the synthetic polyphenol S17834, while increasing SIRT1 deacetylase activity, also increased LKB1 phosphorylation at Ser428 and AMPK activity (Hou et al., 2008).”
AMP-Activated Protein Kinase–Deficient Mice Are Resistant to the Metabolic Effects of Resveratrol (2009, background): “Whether it is the direct target of resveratrol or not, it appears that Sirt1 can also function upstream of AMPK in HepG2 hepatocytes and HEK293T cell line (26,27).”