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.
Pubmed ID: 16753578 RIS Download
Acetylation | Animals | Catalysis | Cell Nucleus | Cells, Cultured | Gene Expression Regulation | Gluconeogenesis | Glucose | Heat-Shock Proteins | Histone Acetyltransferases | Humans | Liver | Male | Mice | Mice, Inbred BALB C | Protein Transport | Trans-Activators | Transcription Factors | Transcription, Genetic