GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha

Cell Metab. 2006 Jun;3(6):429-38. doi: 10.1016/j.cmet.2006.04.013.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Catalysis
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Gene Expression Regulation / physiology
  • Gluconeogenesis / physiology
  • Glucose / antagonists & inhibitors
  • Glucose / metabolism*
  • Heat-Shock Proteins / antagonists & inhibitors
  • Heat-Shock Proteins / genetics*
  • Heat-Shock Proteins / metabolism
  • Histone Acetyltransferases / metabolism
  • Histone Acetyltransferases / physiology*
  • Humans
  • Liver / enzymology
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Protein Transport / physiology
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic / physiology*

Substances

  • Heat-Shock Proteins
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Trans-Activators
  • Transcription Factors
  • Histone Acetyltransferases
  • KAT2A protein, human
  • Glucose