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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

Authors

  • Lerin C
  • Rodgers JT
  • Kalume DE
  • Kim SH
  • Pandey A
  • Puigserver P

Journal

Cell metabolism

Publication Data

June 6, 2006

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK06627

Mesh Terms

  • 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