SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase

Xiuyun Hou, Shanqin Xu, Karlene A. Maitland-Toolan, Kaori Sato, Bingbing Jiang, Yasuo Ido, Fan Lan, Kenneth Walsh, Michel Wierzbicki, Tony J. Verbeuren, Richard A. Cohen, Mengwei Zang

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Pages (from-to)20015-20026
Number of pages12
JournalJournal of Biological Chemistry
Volume283
Issue number29
DOIs
StatePublished - Jul 18 2008
Externally publishedYes

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AMP-Activated Protein Kinases
Lipid Metabolism
Polyphenols
Hepatocytes
Lipids
Fatty Acid Synthases
Phosphorylation
Chemical activation
6,8-diallyl 5,7-dihydroxy 2-(2-allyl 3-hydroxy 4-methoxyphenyl)1-H benzo(b)pyran-4-one
Atherosclerosis
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Acetyl-CoA Carboxylase
Glucose
Liver
Metabolic Diseases
Hep G2 Cells
Medical problems
Dyslipidemias
Hyperlipidemias
Pharmacology

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. / Hou, Xiuyun; Xu, Shanqin; Maitland-Toolan, Karlene A.; Sato, Kaori; Jiang, Bingbing; Ido, Yasuo; Lan, Fan; Walsh, Kenneth; Wierzbicki, Michel; Verbeuren, Tony J.; Cohen, Richard A.; Zang, Mengwei.

In: Journal of Biological Chemistry, Vol. 283, No. 29, 18.07.2008, p. 20015-20026.

Research output: Contribution to journalArticle

Hou, X, Xu, S, Maitland-Toolan, KA, Sato, K, Jiang, B, Ido, Y, Lan, F, Walsh, K, Wierzbicki, M, Verbeuren, TJ, Cohen, RA & Zang, M 2008, 'SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase', Journal of Biological Chemistry, vol. 283, no. 29, pp. 20015-20026. https://doi.org/10.1074/jbc.M802187200
Hou, Xiuyun ; Xu, Shanqin ; Maitland-Toolan, Karlene A. ; Sato, Kaori ; Jiang, Bingbing ; Ido, Yasuo ; Lan, Fan ; Walsh, Kenneth ; Wierzbicki, Michel ; Verbeuren, Tony J. ; Cohen, Richard A. ; Zang, Mengwei. / SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 29. pp. 20015-20026.
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AU - Sato, Kaori

AU - Jiang, Bingbing

AU - Ido, Yasuo

AU - Lan, Fan

AU - Walsh, Kenneth

AU - Wierzbicki, Michel

AU - Verbeuren, Tony J.

AU - Cohen, Richard A.

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