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Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis.

Cell | May 13, 2011

http://www.ncbi.nlm.nih.gov/pubmed/21565617

Class IIa histone deacetylases (HDACs) are signal-dependent modulators of transcription with established roles in muscle differentiation and neuronal survival. We show here that in liver, class IIa HDACs (HDAC4, 5, and 7) are phosphorylated and excluded from the nucleus by AMPK family kinases. In response to the fasting hormone glucagon, class IIa HDACs are rapidly dephosphorylated and translocated to the nucleus where they associate with the promoters of gluconeogenic enzymes such as G6Pase. In turn, HDAC4/5 recruit HDAC3, which results in the acute transcriptional induction of these genes via deacetylation and activation of FOXO family transcription factors. Loss of class IIa HDACs in murine liver results in inhibition of FOXO target genes and lowers blood glucose, resulting in increased glycogen storage. Finally, suppression of class IIa HDACs in mouse models of type 2 diabetes ameliorates hyperglycemia, suggesting that inhibitors of class I/II HDACs may be potential therapeutics for metabolic syndrome.

Pubmed ID: 21565617 RIS Download

Mesh terms: Acetylation | Animals | Cell Nucleus | Diabetes Mellitus, Type 2 | Forkhead Transcription Factors | Glucagon | Gluconeogenesis | Glucose | Histone Deacetylases | Homeostasis | Mice | Phosphorylation | Protein-Serine-Threonine Kinases | Signal Transduction

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Associated grants

  • Agency: NIDDK NIH HHS, Id: DK062434
  • Agency: NICHD NIH HHS, Id: HD027183
  • Agency: NCI NIH HHS, Id: P01 CA120964
  • Agency: NCI NIH HHS, Id: P01 CA120964-02
  • Agency: NCI NIH HHS, Id: P01CA120964
  • Agency: NCI NIH HHS, Id: P30 CA014195
  • Agency: NIDDK NIH HHS, Id: R01 DK049777
  • Agency: NIDDK NIH HHS, Id: R01 DK049777
  • Agency: NIDDK NIH HHS, Id: R01 DK049777-17
  • Agency: NIDDK NIH HHS, Id: R01 DK080425
  • Agency: NIDDK NIH HHS, Id: R01 DK080425
  • Agency: NIDDK NIH HHS, Id: R01 DK080425-02
  • Agency: NIDDK NIH HHS, Id: R01 DK083834
  • Agency: NIDDK NIH HHS, Id: R01 DK083834-25
  • Agency: NICHD NIH HHS, Id: R01 HD027183
  • Agency: NICHD NIH HHS, Id: R01 HD027183-18
  • Agency: NIDDK NIH HHS, Id: R01DK083834
  • Agency: NIDDK NIH HHS, Id: R24 DK090962
  • Agency: NIDDK NIH HHS, Id: R37 DK083834
  • Agency: NIDDK NIH HHS, Id: U19 DK062434
  • Agency: NIDDK NIH HHS, Id: U19 DK062434-09S2
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

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