title: Mechanism of cardiomyocyte PGC-1α gene regulation by ERRα.
abstract: Peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α (PGC-1α) regulates critical genes involved in cardiac mitochondrial biogenesis and fatty acid oxidation, and its loss is associated with impaired metabolism and various cardiac pathologies. Estrogen-related receptor α (ERRα) targets many of the same genes as PGC-1α, and extensive cross talk exists between these 2 regulators. Here we report the identification of an evolutionarily conserved ERRα binding site within the PGC-1α promoter. Using luciferase reporter assays and overexpression, inhibition, or knockdown of ERRα, we show that PGC-1α expression is critically dependent upon ERRα in primary cardiomyocytes. We demonstrate that short-term hypoxia results in reduced ERRα mRNA expression, which precedes a similar loss of PGC-1α mRNA. However, chromatin immunoprecipitation reveals that despite a key role for ERRα in regulating PGC-1α in normoxic cardiomyocytes, ERRα loss is not responsible for PGC-1α loss in hypoxia. Histone deacetylase 5 (HDAC5) has previously been demonstrated to strongly inhibit expression of PGC-1α, and we show that overexpression of ERRα is sufficient to overcome this repressive effect. Our data elucidates the mechanism by which ERRα regulates cardiac PGC-1α gene expression, and suggests that ERRα may provide a means to normalize PGC-1α expression that could be useful in the development of strategies aimed at improving cardiac metabolism in disease.
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre and Department of Physiology, University of Manitoba, 351 Tache Avenue, Winnipeg, MB R2H 2A6, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: Ramjiawan
authors.forename: Rushita A
authors.initials: RA
authors.lastname: Bagchi
authors.forename: Laura
authors.initials: L
authors.lastname: Albak
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czubryt
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D032383:Myocytes, Cardiac / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000502:physiology*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D017931:DNA Primers; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C501429:Ppargc1a protein, rat