Regulation of PPARγ coactivator 1α (PGC-1α) signaling by an estrogen-related receptor α (ERRα) ligand
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) is a transcriptional coactivator that is a key component in the regulation of energy production and utilization in metabolic tissues. Recent work has identified PGC-1α as a strong coactivator of the orphan nuclear receptor estrogen-related receptor α (ERRα), implicating ERRα as a potential mediator of PGC-1α action. To understand the role of ERRα in PGC-1α signaling, a parallel approach of high-throughput screening and gene-expression analysis was used to identify ERRα small-molecule regulators and target genes. We report here the identification of a potent and selective ERRα inverse agonist that interferes effectively with PGC-1α/ERRα-dependent signaling. This inverse agonist inhibits the constitutive activity of ERRα in both biochemical and cell-based assays. Also, we demonstrate that monoamine oxidase B is an ERRα target gene whose expression is regulated by PGC-1α and ERRα and inhibited by the ERRα inverse agonist. The discovery of potent and selective ERRα modulators and their effect on PGC-1α signaling provides mechanistic insight into gene regulation by PGC-1α. These findings validate ERRα as a promising therapeutic target in the treatment of metabolic disorders, including diabetes and obesity.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- June 2004
- DOI:
- 10.1073/pnas.0401420101
- Bibcode:
- 2004PNAS..101.8912W
- Keywords:
-
- BIOCHEMISTRY