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

Abstract

SUMMARY 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.

Deleted in Breast Cancer 1 (DBC1) Protein Regulates Hepatic Gluconeogenesis

“…In the fasted state, and in the DBC1 KO mice, increased SIRT1 activity could result in deacetylation of PGC1␣ (21) and FOXO (28), which would also result in higher glucose production. Moreover, it is possible that DBC1 also regulates gluconeogenesis through histone deacetylase 3 (HDAC3), which is inhibited by DBC1 (16) and has been shown to promote glucose production (40,41). In addition, it could also be that changes in the levels of DBC1, or changes to its binding partners, result in alterations in the epigenetic landscape of the PEPCK promoter.…”

Identification of an epigenetic signature of early mouse liver regeneration that is disrupted by Zn-HDAC inhibition

“…7,23,27 In addition, HDAC5 undergoes PH-induced nuclear localization in regenerating liver, 2 and this Zn-HDAC also exhibits hypoglycemia-induced nuclear localization and regulates FOXO target gene expression in other models. 28 Finally, recent studies suggest that specific metabolites modulate isoformspecific HDAC activity in vivo. 29 Together, these considerations suggest that investigating patterns of liver histone acetylation in experimental models in which PH-induced alterations in metabolism are disrupted and regeneration is impaired could further elucidate epigenetic mechanisms linking metabolism and established pro-regenerative signaling pathways to liver regeneration.…”

Post-translational modifications of FOXO family proteins

“…Generally, HDAC1 is able to complex with HDAC2 to exert normal functions. In addition, HDAC4/5 recruits HDAC3 and FOXO proteins to form a complex, allowing it to be deacetylated and activated (80). It has been reported that HDAC1 is a primary regulator of FOXO in skeletal muscle and a key regulator of the atrophy.…”