Article

Class IIa Histone Deacetylases Are Hormone-Activated Regulators of FOXO and Mammalian Glucose Homeostasis

Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Cell (Impact Factor: 32.24). 05/2011; 145(4):607-21. DOI: 10.1016/j.cell.2011.03.043
Source: PubMed

ABSTRACT

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.

Full-text

Available from: Michael Downes
  • Source
    • "FOXO1 export from nuclei occurs with phosphorylation by AKT or through acetylation [26]. In K ATP channel deficient skeletal muscles of TG mice, total FOXO1 is not different from controls (Fig. 2B, E; .72±.03, .69±.05, .67±.02 AU, for WT, GFP and TG respectively, n=4 each, p=NS for all comparisons), however acetylated FOXO1 is significantly increased (Fig. 2C and activation of FOXO1 [28]. The nuclear export of FOXO1 in TG is also paralleled by an elevated presence of CaMKII activated by phosphorylation (p-CaMKII), a negative regulator of HDAC4 nuclear localization [29]. "
    [Show description] [Hide description] DESCRIPTION: Disruption of ATP-sensitive potassium channel function in skeletal muscles promotes production and secretion of musclin
    Full-text · Research · Feb 2016
  • Source
    • "FOXO1 export from nuclei occurs with phosphorylation by AKT or through acetylation [26]. In K ATP channel deficient skeletal muscles of TG mice, total FOXO1 is not different from controls (Fig. 2B, E; .72±.03, .69±.05, .67±.02 AU, for WT, GFP and TG respectively, n=4 each, p=NS for all comparisons), however acetylated FOXO1 is significantly increased (Fig. 2C and activation of FOXO1 [28]. The nuclear export of FOXO1 in TG is also paralleled by an elevated presence of CaMKII activated by phosphorylation (p-CaMKII), a negative regulator of HDAC4 nuclear localization [29]. "
    Full-text · Article · Jan 2016 · Biochemical and Biophysical Research Communications
  • Source
    • "Exercise induced a similar increase in NAD + content and a decrease in acetylation of p53, implying a similar activation of the NAD + dependent deacetylase SIRT1 in both genotypes. Likewise, exercise decreased HDAC4 phosphorylation similarly in the two genotypes, which is expected to result in a similar exclusion of HDAC4 from the nucleus, thereby activating the FoxO1 transcription factor (Mihaylova et al. 2011) and accordingly inducing PDK4 transcription. Collectively, this supports the finding of a similar exercise-induced increase in PDK4 mRNA in the two genotypes. "
    [Show abstract] [Hide abstract] ABSTRACT: It is well known that exercise has a major impact on substrate metabolism for many hours after exercise. However, the regulatory mechanisms increasing lipid oxidation and facilitating glycogen resynthesis in the post-exercise period are unknown. To address this, substrate oxidation was measured after prolonged exercise and during the following six hours post exercise in 5´AMP activated protein kinase (AMPK)α2 and α1 knock-out (KO) and wild type (WT) mice with free access to food. Substrate oxidation was similar during exercise at the same relative intensity between genotypes. During post-exercise recovery, a lower lipid oxidation (P < 0.05) and higher glucose oxidation were observed in AMPKα2 KO (respiratory exchange ratio (RER) = 0.84 ± 0.02) than in WT and AMPKα1 KO (average RER = 0.80 ± 0.01) without genotype differences in muscle malonyl CoA or free-carnitine concentrations. A similar increase in muscle pyruvate dehydrogenase kinase 4 (PDK4) mRNA expression in WT and AMPKα2 KO was observed following exercise, which is consistent with AMPKα2-deficiency not affecting the exercise-induced activation of the PDK4 transcriptional regulators, HDAC4 and SIRT1. Interestingly, PDK4 protein content increased (63 %, P < 0.001) in WT but remained unchanged in AMPKα2 KO. In accordance with the lack of increase in PDK4 protein content, lower (P < 0.01) inhibitory pyruvate dehydrogenase (PDH)-E1α Ser293 phosphorylation was observed in AMPKα2 KO muscle compared to WT. These findings indicate that AMPKα2 regulates muscle metabolism post-exercise through inhibition of the PDH complex and hence glucose oxidation, subsequently creating conditions for increased fatty acid oxidation.This article is protected by copyright. All rights reserved
    Full-text · Article · Sep 2015 · The Journal of Physiology
Show more