Proatherogenic abnormalities of lipid metabolism in SirT1 transgenic mice are mediated through Creb deacetylation.
Proatherogenic abnormalities of lipid metabolism in SirT1 transgenic mice are mediated through Creb deacetylation.
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DOI：
10.1016/j.cmet.2011.10.007
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发表时间：
2011-12-07
期刊：
影响因子：
29
通讯作者：
Accili D
中科院分区：
文献类型：
--
作者：
Qiang L;Lin HV;Kim-Muller JY;Welch CL;Gu W;Accili D
血脂异常和动脉粥样硬化与胰岛素敏感性降低和糖尿病有关，但其机制尚不清楚。编码去乙酰化酶SirT1的基因的功能获得可改善胰岛素敏感性，并有望防止脂质异常。令人惊讶的是，当过表达SirT1 （SirBACO）的转基因小鼠被置于致动脉粥样硬化饮食中时，它们维持了更好的葡萄糖稳态，但出现了更差的脂质谱和更大的动脉粥样硬化病变。我们发现转录因子cAMP反应元件结合蛋白（Creb）在SirBACO小鼠中去乙酰化。我们发现Lys136是sirt1依赖性去乙酰化的底物，通过阻止其camp依赖性磷酸化影响Creb活性，导致糖原基因表达减少，促进肝脏脂质积累和分泌。在SirBACO小鼠中，组成性乙酰化的Creb （K136Q）的表达模拟了Creb的激活，并消除了SirT1功能获得的血脂异常和胰岛素增敏作用。我们提出sirt1依赖性Creb去乙酰化调节糖脂代谢平衡，整合空腹信号。
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.
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影响因子：
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通讯作者：
Accili D