GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha.
Hormonal and nutrient regulation of hepatic gluconeogenesis mainly occurs through modulation of the transcriptional coactivator PGC-1alpha. The identity of endogenous proteins and their enzymatic activities that regulate the functions and form part of PGC-1alpha complex are unknown. Here, we show that PGC-1alpha is in a multiprotein complex containing the acetyltransferase GCN5. PGC-1alpha is directly acetylated by GCN5 resulting in a transcriptionally inactive protein that relocalizes from promoter regions to nuclear foci. Adenoviral-mediated expression of GCN5 in cultured hepatocytes and in mouse liver largely represses activation of gluconeogenic enzymes and decreases hepatic glucose production. Thus, we have identified the endogenous PGC-1alpha protein complex and provided the molecular mechanism by which PGC-1alpha acetylation by GCN5 turns off the transcriptional and biological function of this metabolic coactivator. GCN5 might be a pharmacological target to regulate the activity of PGC-1alpha, providing a potential treatment for metabolic disorders in which hepatic glucose output is dysregulated.
Lerin
Carles
C
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Rodgers
Joseph T
JT
Kalume
Dario E
DE
Kim
Seung-hee
SH
Pandey
Akhilesh
A
Puigserver
Pere
P
D000107:Acetylation; D000818:Animals; D002384:Catalysis; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D005943:Gluconeogenesis / Q000502:physiology; D005947:Glucose / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D021381:Protein Transport / Q000502:physiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*; D000099224:p300-CBP-Associated Factor
D005947:Glucose; D006360:Heat-Shock Proteins; D051548:Histone Acetyltransferases; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators; D014157:Transcription Factors; C486497:PPARGC1A protein, human; C485290:Ppargc1a protein, mouse; C501179:KAT2A protein, human; D000099224:p300-CBP-Associated Factor