Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1a
Por:
Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, Alt FW, Wu Z and Puigserver P
Publicada:
4 abr 2007
Resumen:
In mammals, maintenance of energy and nutrient homeostasis during food deprivation is accomplished through an increase in mitochondrial fatty acid oxidation in peripheral tissues. An important component that drives this cellular oxidative process is the transcriptional coactivator PGC-1 alpha. Here, we show that fasting induced PGC-1 alpha deacetylation in skeletal muscle and that SIRT1 deacetylation of PGC-1 alpha is required for activation of mitochondrial fatty acid oxidation genes. Moreover, expression of the acetyltransferase, GCN5, or the SIRT1 inhibitor, nicotinamide, induces PGC-1 alpha acetylation and decreases expression of PGC-1 alpha target genes in myotubes. Consistent with a switch from glucose to fatty acid oxidation that occurs in nutrient deprivation states, SIRT1 is required for induction and maintenance of fatty acid oxidation in response to low glucose concentrations. Thus, we have identified SIRT1 as a functional regulator of PGC-1 alpha that induces a metabolic gene transcription program of mitochondrial fatty acid oxidation. These results have implications for understanding selective nutrient adaptation and how it might impact lifespan or metabolic diseases such as obesity and diabetes.
Filiaciones:
Harvard Univ, Sch Med, Dept Cell Biol, Dana Farber Canc Inst, Boston, MA 02115 USA
Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD USA
Novartis Inst Biomed Res Inc, Cambridge, MA USA
Harvard Univ, Sch Med, Childrens Hosp, CBR Inst Biomed Res,Dept Genet,Howard Hughes Med, Boston, MA 02115 USA
Green Submitted, Bronze
|