The GCN5-CITED2-PKA signalling module controls hepatic glucose metabolism through a cAMP-induced substrate switch

Nat Commun. 2016 Nov 22;7:13147. doi: 10.1038/ncomms13147.


Hepatic gluconeogenesis during fasting results from gluconeogenic gene activation via the glucagon-cAMP-protein kinase A (PKA) pathway, a process whose dysregulation underlies fasting hyperglycemia in diabetes. Such transcriptional activation requires epigenetic changes at promoters by mechanisms that have remained unclear. Here we show that GCN5 functions both as a histone acetyltransferase (HAT) to activate fasting gluconeogenesis and as an acetyltransferase for the transcriptional co-activator PGC-1α to inhibit gluconeogenesis in the fed state. During fasting, PKA phosphorylates GCN5 in a manner dependent on the transcriptional coregulator CITED2, thereby increasing its acetyltransferase activity for histone and attenuating that for PGC-1α. This substrate switch concomitantly promotes both epigenetic changes associated with transcriptional activation and PGC-1α-mediated coactivation, thereby triggering gluconeogenesis. The GCN5-CITED2-PKA signalling module and associated GCN5 substrate switch thus serve as a key driver of gluconeogenesis. Disruption of this module ameliorates hyperglycemia in obese diabetic animals, offering a potential therapeutic strategy for such conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cells, Cultured
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Diabetes Mellitus, Type 2 / chemically induced
  • Diet, High-Fat / adverse effects
  • Gene Expression Regulation / drug effects
  • Gluconeogenesis / physiology
  • Glucose / metabolism*
  • Hepatocytes / physiology
  • Humans
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism*


  • Cited2 protein, mouse
  • Repressor Proteins
  • Trans-Activators
  • Cyclic AMP
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Cyclic AMP-Dependent Protein Kinases
  • Glucose