Rodgers Joseph T, Lerin Carlos, Haas Wilhelm, Gygi Steven P, Spiegelman Bruce M, Puigserver Pere
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Nature. 2005 Mar 3;434(7029):113-8. doi: 10.1038/nature03354.
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--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.
哺乳动物体内的稳态机制通过对激素和营养物质做出反应，将血糖水平维持在一个狭窄的范围内。热量限制会引起葡萄糖代谢的诸多变化，并延长寿命；然而，这种代谢与衰老过程之间的联系在很大程度上仍不为人知。我们在此表明，Sir2同源物SIRT1（它在多个物种中调节衰老）通过转录共激活因子PGC-1α，响应禁食信号来控制肝脏中的糖异生/糖酵解途径。禁食期间，由丙酮酸介导的一种营养信号反应会在肝脏中诱导SIRT1蛋白。我们发现，一旦SIRT1被诱导，它就会以NAD⁺依赖的方式与PGC-1α在特定赖氨酸残基处相互作用并使其去乙酰化。SIRT1通过PGC-1α诱导糖异生基因和肝脏葡萄糖输出，但不调节PGC-1α对线粒体基因的影响。此外，SIRT1调节PGC-1α对糖酵解基因的抑制作用，以响应禁食和丙酮酸。因此，我们确定了一种分子机制，通过该机制SIRT1作为PGC-1α的调节剂在葡萄糖稳态中发挥作用。这些发现对能量稳态、糖尿病和寿命的基本途径具有重要意义。
