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

被引：480

作者：

Mihaylova, Maria M. ^{[1
,5
]}

Vasquez, Debbie S. ^{[1
,5
]}

Ravnskjaer, Kim ^{[2
,5
]}

Denechaud, Pierre-Damien ^{[1
,5
]}

Yu, Ruth T. ^{[3
,5
]}

Alvarez, Jacqueline G. ^{[3
,5
]}

Downes, Michael ^{[3
,5
]}

Evans, Ronald M. ^{[3
,4
,5
]}

Montminy, Marc ^{[2
,5
]}

Shaw, Reuben J. ^{[1
,4
,5
]}

机构：

[1] Salk Inst Biol Studies, Mol & Cell Biol Lab, La Jolla, CA 92037 USA

[2] Salk Inst Biol Studies, Clayton Labs Peptide Biol, La Jolla, CA 92037 USA

[3] Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA

[4] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA

[5] Salk Inst Biol Studies, Leona & Harry Helmsley Ctr Nutr Genom, La Jolla, CA 92037 USA

来源：

CELL | 2011年 / 145卷 / 04期

关键词：

CREB COACTIVATOR TORC2; STEM-CELL HOMEOSTASIS; PROTEIN-KINASE; TRANSCRIPTION FACTOR; METABOLIC SYNDROME; GENE-EXPRESSION; CLASS IIHDAC; PHOSPHORYLATION; ACETYLATION; DISEASE;

D O I：

10.1016/j.cell.2011.03.043

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：607 / 621

页数：15

共 55 条

[1] SIK1 is a class IIHDAC kinase that promotes survival of skeletal myocytes [J].