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

@article{citeulike:2811166, 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, acetyl CoA carboxylase (ACC), elevation in expression of fatty acid synthase (FAS), 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 CaMKK-beta, 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.}, address = {Department of Medicine, Boston University School of Medicine, Boston, MA 02481.}, author = {Hou, Xiuyun and Xu, Shanqin and Maitland-Toolan, Karlene A A. and Sato, Kaori and Jiang, Bingbing and Ido, Yasuo and Lan, Fan and Walsh, Kenneth and Wierzbicki, Michel and Verbeuren, Tony J J. and Cohen, Richard A A. }, citeulike-article-id = {2811166}, doi = {http://dx.doi.org/10.1074/jbc.M802187200}, issn = {0021-9258}, journal = {The Journal of biological chemistry}, keywords = {metabolism, sirt1}, month = {May}, posted-at = {2008-05-18 22:10:53}, priority = {2}, title = {SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase.}, url = {http://dx.doi.org/10.1074/jbc.M802187200}, year = {2008} }

TY - JOUR ID - citeulike:2811166 L3 - citeulike-article-id:2811166 N2 - 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, acetyl CoA carboxylase (ACC), elevation in expression of fatty acid synthase (FAS), 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 CaMKK-beta, 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. JF - The Journal of biological chemistry SN - 0021-9258 AD - Department of Medicine, Boston University School of Medicine, Boston, MA 02481. TI - SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. KW - metabolism KW - sirt1 AU - Hou, Xiuyun AU - Xu, Shanqin AU - Maitland-Toolan, Karlene A 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 PY - 2008/05/14/ UR - http://dx.doi.org/10.1074/jbc.M802187200 ER -