Journal
EXPERT OPINION ON THERAPEUTIC PATENTS
Volume 21, Issue 10, Pages 1651-1656Publisher
INFORMA HEALTHCARE
DOI: 10.1517/13543776.2011.602069
Keywords
epigenetics; GCN5 inhibitor; metabolic disorders; PGC-1 alpha; SIRT1 activator
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Funding
- Istituto Pasteur - Fondazione Cenci Bolognetti
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The transcriptional peroxisome proliferator-activated receptor gamma (PPAR gamma) co-activator PGC-1 alpha plays a central role in the regulation of cellular energy metabolism. Among the wide range of its activities, PGC-1 alpha controls mitochondrial biogenesis and function and is one of the main factors involved in hormonal and nutrient regulation of hepatic gluconeogenesis. PGC-1 alpha is present in a multiprotein complex, and its activity can also be modulated through epigenetic modifications. In particular, it is directly acetylated by the HAT enzyme general control nonderepressible 5 (GCN5), resulting in a transcriptionally inactive protein that relocalizes from promoter regions to nuclear foci, whereas it is deacetylated by SIRT1 at multiple lysine sites, with a subsequent increase in its activity leading to induction of liver gluconeogenic gene transcription. Thus, both GCN5 and SIRT1 may be pharmacological targets to regulate the activity of PGC-1 alpha, providing a potential treatment for metabolic disorders in which hepatic glucose output is altered.
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