Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha.
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-1alpha. Here, we show that fasting induced PGC-1alpha deacetylation in skeletal muscle and that SIRT1 deacetylation of PGC-1alpha is required for activation of mitochondrial fatty acid oxidation genes. Moreover, expression of the acetyltransferase, GCN5, or the SIRT1 inhibitor, nicotinamide, induces PGC-1alpha acetylation and decreases expression of PGC-1alpha 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-1alpha 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.
Gerhart-Hines
Zachary
Z
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, One Jimmy Fund Way, Boston, MA 02115, USA.
Rodgers
Joseph T
JT
Bare
Olivia
O
Lerin
Carles
C
Kim
Seung-Hee
SH
Mostoslavsky
Raul
R
Alt
Frederick W
FW
Wu
Zhidan
Z
Puigserver
Pere
P
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000102:Acetyl-CoA C-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D000107:Acetylation / Q000187:drug effects; D000818:Animals; D019748:Carbon-Carbon Double Bond Isomerases / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004746:Enoyl-CoA Hydratase / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D051548:Histone Acetyltransferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D019998:Racemases and Epimerases / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D015094:3-Hydroxyacyl CoA Dehydrogenases; D000102:Acetyl-CoA C-Acyltransferase; D019748:Carbon-Carbon Double Bond Isomerases; D018797:Cell Cycle Proteins; D004746:Enoyl-CoA Hydratase; D005947:Glucose; D051548:Histone Acetyltransferases; D009536:Niacinamide; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D019998:Racemases and Epimerases; D056564:Sirtuin 1; D037761:Sirtuins; D015534:Trans-Activators; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C485290:Ppargc1a protein, mouse; C038784:fatty acid oxidation complex; C470545:Sirt1 protein, mouse