title: Epigenetic modulation of PGC-1α activity by GCN5 inhibitors: WO2010007085.
abstract: The transcriptional peroxisome proliferator-activated receptor γ (PPARγ) co-activator PGC-1α plays a central role in the regulation of cellular energy metabolism. Among the wide range of its activities, PGC-1α controls mitochondrial biogenesis and function and is one of the main factors involved in hormonal and nutrient regulation of hepatic gluconeogenesis. PGC-1α 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-1α, providing a potential treatment for metabolic disorders in which hepatic glucose output is altered.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P. A. Moro 5, 00185 Rome, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Carradori
authors.forename: Daniela
authors.initials: D
authors.lastname: Secci
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems; D015195:Drug Design; D044127:Epigenesis, Genetic; D005947:Glucose / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008659:Metabolic Diseases / Q000188:drug therapy / Q000503:physiopathology; D010330:Patents as Topic; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D056564:Sirtuin 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D005947:Glucose; D006360:Heat-Shock Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D056564:Sirtuin 1; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C486497:PPARGC1A protein, human; C447939:SIRT1 protein, human