title: SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism.
abstract: The SIRT1 deacetylase inhibits fat synthesis and stimulates fat oxidation in response to fasting, but the underlying mechanisms remain unclear. Here we report that SREBP-1c, a key lipogenic activator, is an in vivo target of SIRT1. SIRT1 interaction with SREBP-1c was increased during fasting and decreased upon feeding, and consistently, SREBP-1c acetylation levels were decreased during fasting in mouse liver. Acetylated SREBP-1c levels were also increased in HepG2 cells treated with insulin and glucose to mimic feeding conditions, and down-regulation of p300 by siRNA decreased the acetylation. Depletion of hepatic SIRT1 by adenoviral siRNA increased acetylation of SREBP-1c with increased lipogenic gene expression. Tandem mass spectrometry and mutagenesis studies revealed that SREBP-1c is acetylated by p300 at Lys-289 and Lys-309. Mechanistic studies using acetylation-defective mutants showed that SIRT1 deacetylates and inhibits SREBP-1c transactivation by decreasing its stability and its occupancy at the lipogenic genes. Remarkably, SREBP-1c acetylation levels were elevated in diet-induced obese mice, and hepatic overexpression of SIRT1 or treatment with resveratrol, a SIRT1 activator, daily for 1 week decreased acetylated SREBP-1c levels with beneficial functional outcomes. These results demonstrate an intriguing connection between elevated SREBP-1c acetylation and increased lipogenic gene expression, suggesting that abnormally elevated SREBP-1c acetylation increases SREBP-1c lipogenic activity in obese mice. Reducing acetylation of SREBP-1c by targeting SIRT1 may be useful for treating metabolic disorders, including fatty liver, obesity, and type II diabetes.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois 61801, USA.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Ponugoti
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xiao
authors.forename: Zachary
authors.initials: Z
authors.lastname: Smith
authors.forename: Ji
authors.initials: J
authors.lastname: Miao
authors.forename: Mengwei
authors.initials: M
authors.lastname: Zang
authors.forename: Shwu-Yuan
authors.initials: SY
authors.lastname: Wu
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chiang
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Veenstra
authors.forename: Jongsook Kim
authors.initials: JK
authors.lastname: Kemper
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008099:Liver / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D056564:Sirtuin 1 / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*
chemical_list: D007328:Insulin; D008055:Lipids; D051780:Sterol Regulatory Element Binding Protein 1; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
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