Open AccessRegulation of PPARγ coactivator 1α (PGC-1α) signaling by an estrogen-related receptor α (ERRα) ligand
Author(s) -
Patricia J. Willy,
Ian R. Murray,
Jing Qian,
Brett B. Busch,
William C. Stevens,
Richard Martin,
Raju Mohan,
Sihong Zhou,
Peter Ordentlich,
Ping Wei,
Douglas W. Sapp,
Robert A. Horlick,
Richard A. Heyman,
Ira G. Schulman
Publication year - 2004
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0401420101
Subject(s) - coactivator , nuclear receptor , estrogen related receptor alpha , peroxisome proliferator activated receptor , inverse agonist , agonist , receptor , mediator , signal transduction , biology , microbiology and biotechnology , transcription factor , estrogen receptor , gene , biochemistry , genetics , cancer , breast cancer
Peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha) 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-1alpha as a strong coactivator of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha), implicating ERRalpha as a potential mediator of PGC-1alpha action. To understand the role of ERRalpha in PGC-1alpha signaling, a parallel approach of high-throughput screening and gene-expression analysis was used to identify ERRalpha small-molecule regulators and target genes. We report here the identification of a potent and selective ERRalpha inverse agonist that interferes effectively with PGC-1alpha/ERRalpha-dependent signaling. This inverse agonist inhibits the constitutive activity of ERRalpha in both biochemical and cell-based assays. Also, we demonstrate that monoamine oxidase B is an ERRalpha target gene whose expression is regulated by PGC-1alpha and ERRalpha and inhibited by the ERRalpha inverse agonist. The discovery of potent and selective ERRalpha modulators and their effect on PGC-1alpha signaling provides mechanistic insight into gene regulation by PGC-1alpha. These findings validate ERRalpha as a promising therapeutic target in the treatment of metabolic disorders, including diabetes and obesity.