Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1
Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1
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DOI：
10.1038/nature03354
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发表时间：
2005-03-03
期刊：
影响因子：
64.8
通讯作者：
Puigserver, P
中科院分区：
文献类型：
--
作者：
Rodgers, JT;Lerin, C;Puigserver, P
哺乳动物的稳态机制对激素和营养作出反应，以将血糖水平保持在狭窄范围内。热量限制会导致葡萄糖代谢的许多变化，并延长寿命。但是，这种新陈代谢如何与衰老过程有关。我们在这里表明，SIR2同源物SIRT1-调节几种物种的衰老（1-3） - 控制肝脏中的糖原性/糖酵解途径，响应通过转录共激活器PGC -1Alpha响应禁食信号。丙酮酸介导的营养信号反应在禁食过程中诱导肝脏中的SIRT1蛋白。我们发现，一旦诱导了SIRT1，它就会与NAD（+）依赖性方式的特定赖氨酸残基上的PGC-1Alpha相互作用并脱乙酰基PGC-1Alpha。 SIRT1通过PGC-1Alpha诱导糖原性基因和肝葡萄糖输出，但不调节PGC-1Alpha对线粒体基因的影响。另外，SIRT1调节糖酵解基因对禁食和丙酮酸的糖酵解基因的抑制作用。因此，我们确定了一种分子机制，SIRT1在葡萄糖稳态中起作用，作为PGC-1Alpha的调节剂。这些发现对能量稳态，糖尿病和寿命的基本途径具有很大的影响。
Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 homologue, SIRT1 - which modulates ageing in several species(1-3) - controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1alpha. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1alpha at specific lysine residues in an NAD(+)-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1alpha, but does not regulate the effects of PGC-1alpha on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate. Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1alpha. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.