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Cell Metab. 2006 Jun;3(6):429-38.

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

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1
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

Abstract

Hormonal and nutrient regulation of hepatic gluconeogenesis mainly occurs through modulation of the transcriptional coactivator PGC-1alpha. The identity of endogenous proteins and their enzymatic activities that regulate the functions and form part of PGC-1alpha complex are unknown. Here, we show that PGC-1alpha is in a multiprotein complex containing the acetyltransferase GCN5. PGC-1alpha 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-1alpha protein complex and provided the molecular mechanism by which PGC-1alpha 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-1alpha, providing a potential treatment for metabolic disorders in which hepatic glucose output is dysregulated.

PMID:
16753578
DOI:
10.1016/j.cmet.2006.04.013
[Indexed for MEDLINE]
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