title: Proatherogenic abnormalities of lipid metabolism in SirT1 transgenic mice are mediated through Creb deacetylation.
abstract: Dyslipidemia and atherosclerosis are associated with reduced insulin sensitivity and diabetes, but the mechanism is unclear. Gain of function of the gene encoding deacetylase SirT1 improves insulin sensitivity and could be expected to protect against lipid abnormalities. Surprisingly, when transgenic mice overexpressing SirT1 (SirBACO) are placed on atherogenic diet, they maintain better glucose homeostasis, but develop worse lipid profiles and larger atherosclerotic lesions than controls. We show that transcription factor cAMP response element binding protein (Creb) is deacetylated in SirBACO mice. We identify Lys136 is a substrate for SirT1-dependent deacetylation that affects Creb activity by preventing its cAMP-dependent phosphorylation, leading to reduced expression of glucogenic genes and promoting hepatic lipid accumulation and secretion. Expression of constitutively acetylated Creb (K136Q) in SirBACO mice mimics Creb activation and abolishes the dyslipidemic and insulin-sensitizing effects of SirT1 gain of function. We propose that SirT1-dependent Creb deacetylation regulates the balance between glucose and lipid metabolism, integrating fasting signals.
authors.affiliation: Naomi Berrie Diabetes Center, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qiang
authors.forename: Hua V
authors.initials: HV
authors.lastname: Lin
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Kim-Muller
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Welch
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D050171:Dyslipidemias / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D005947:Glucose
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