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 species1,2,3 —controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1α. 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-1α at specific lysine residues in an NAD+-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1α, but does not regulate the effects of PGC-1α on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1α 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-1α. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.
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We thank P. Vazquez for important discussions on the project. We also acknowledge members of the Puigserver laboratory for helpful comments on this work, especially T. Cunningham and S.-H. Kim for technical assistance. Some constructs or reagents were obtained from W. Gu, L. Guarente, D. Robinson and M. Stoffel. We also thank M. Montminy for the PGC-1α polyclonal antibody. The protocols for NAD+ and NADH measurements were obtained from S.-J. Lin. Part of these studies was supported by awards from the Ellison Medical Foundation and the American Federation for Aging Research (P.P.).
The authors declare that they have no competing financial interests.
SIRT1 protein is not regulated by forskolin/dexamethasone or insulin. (PDF 43 kb)
SIRT1 regulation at the protein level. A. Pulse-chase experiment showing that incubation in pyruvate does not change SIRT1 half-life. B. Pulse labelling experiment showing an increase in labelled SIRT1 when pyruvate is added to pulse media. (PDF 195 kb)
In-vivo and In-vitro interaction of SIRT1 and PGC-1α. A. In-vivo interaction of overexpressed SIRT1 and PGC-1α in 293T cells. B. In-vitro interaction of 35S labelled SIRT1 and GST-PGC-1α. (PDF 119 kb)
Mapping of PGC-1α acetylation sites. A. Identified acetylated PGC-1α peptides. B. Identification of acetylation at PGC-1α residue K183. (PDF 112 kb)
SIRT1 is in a complex that includes PGC-1α and HNF4α. A. In 293T cells endogenous SIRT1 co-immunoprecipitates with HNF4α only when PGC-1α is overexpressed. B. Immunoprecipitation of endogenous SIRT1 pulls down endogenous PGC-1α and HNF4α in FAO cells. (PDF 106 kb)
SIRT1 siRNA decreases SIRT1 levels but does not affect PGC-1α protein. (PDF 49 kb)
Chromatin immunoprecipitation of SIRT1 and PGC-1α showing both are present on gluconeogenic promoters. (PDF 60 kb)
Table of RT-PCR primers. (PDF 12 kb)
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