GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1α

被引:360
作者
Lerin, Caries
Rodgers, Joseph T.
Kalume, Dario E.
Kim, Seung-Hee
Pandey, Akhilesh
Puigserver, Pere [1 ]
机构
[1] Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA
[3] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA
关键词
D O I
10.1016/j.cmet.2006.04.013
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Hormonal and nutrient regulation of hepatic gluconeogenesis mainly occurs through modulation of the transcriptional coactivator PGC-1 alpha. The identity of endogenous proteins and their enzymatic activities that regulate the functions and form part of PGC-1 alpha complex are unknown. Here, we show that PGC-1 alpha is in a multiprotein complex containing the acetyltransferase GCN5. PGC-1 alpha is directly acetylated by GCN5 resulting in a transcriptionally inactive protein that relocalizes from promoter regions to nuclear foci. Adenoviral-mediated expression of GCN5 in cultured hepatocytes and in mouse liver largely represses activation of gluconeogenic enzymes and decreases hepatic glucose production. Thus, we have identified the endogenous PGC-1 alpha protein complex and provided the molecular mechanism by which PGC-1 alpha acetylation by GCN5 turns off the transcriptional and biological function of this metabolic coactivator. GCN5 might be a pharmacological target to regulate the activity of PGC-1 alpha, providing a potential treatment for metabolic disorders in which hepatic glucose output is dysregulated.
引用
收藏
页码:429 / 438
页数:10
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