Proatherogenic Abnormalities of Lipid Metabolism in SirT1 Transgenic Mice Are Mediated through Creb Deacetylation

• Published in: Cell metabolism Vol. 14; no. 6; pp. 758 - 767
• Main Authors: Qiang, Li, Lin, Hua V., Kim-Muller, Ja Young, Welch, Carrie L., Gu, Wei, Accili, Domenico
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.12.2011
• Subjects: Animals; Atherosclerosis - genetics; Atherosclerosis - metabolism; Blotting, Western; Cyclic AMP Response Element-Binding Protein - metabolism; Dyslipidemias - genetics; Dyslipidemias - metabolism; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation - physiology; Glucose - metabolism; HEK293 Cells; Humans; Immunohistochemistry; Immunoprecipitation; Insulin Resistance - genetics; Insulin Resistance - physiology; Lipid Metabolism - genetics; Lipid Metabolism - physiology; Mice; Mice, Transgenic; Phosphorylation; Rats; Real-Time Polymerase Chain Reaction; Sirtuin 1 - metabolism
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2011.10.007

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. ▸ SirT1 gain of function predisposes to dyslipidemia and atherosclerosis ▸ SirT1 deacetylates cAMP response element binding protein (Creb) on Lys136 ▸ Constitutively acetylated CREB mutant K136Q lowers plasma lipids in SirT1 transgenics ▸ CREB acetylation integrates cAMP-dependent with SirT1-dependent fasting responses