Nutrient control of glucose homeostasis through a complex of PGC-1[alpha] and SIRT1.
Rodgers, Joseph T. 1; Lerin, Carlos 1; Haas, Wilhelm 3; Gygi, Steven P. 3; Spiegelman, Bruce M. 2,3; Puigserver, Pere 1
[Letter] Nature. 434(7029):113-118, March 3, 2005.

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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-1[alpha]. 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-1[alpha] at specific lysine residues in an NAD -dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1[alpha], but does not regulate the effects of PGC-1[alpha] on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1[alpha] 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-1[alpha]. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.

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