期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：24
页码：8912-8917
DOI：10.1073/pnas.0401420101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) coactivator 1{alpha} (PGC-1{alpha}) 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-1{alpha} as a strong coactivator of the orphan nuclear receptor estrogen-related receptor {alpha} (ERR{alpha}), implicating ERR{alpha} as a potential mediator of PGC-1{alpha} action. To understand the role of ERR{alpha} in PGC-1{alpha} signaling, a parallel approach of high-throughput screening and gene-expression analysis was used to identify ERR{alpha} small-molecule regulators and target genes. We report here the identification of a potent and selective ERR{alpha} inverse agonist that interferes effectively with PGC-1{alpha}/ERR{alpha}-dependent signaling. This inverse agonist inhibits the constitutive activity of ERR{alpha} in both biochemical and cell-based assays. Also, we demonstrate that monoamine oxidase B is an ERR{alpha} target gene whose expression is regulated by PGC-1{alpha} and ERR{alpha} and inhibited by the ERR{alpha} inverse agonist. The discovery of potent and selective ERR{alpha} modulators and their effect on PGC-1{alpha} signaling provides mechanistic insight into gene regulation by PGC-1{alpha}. These findings validate ERR{alpha} as a promising therapeutic target in the treatment of metabolic disorders, including diabetes and obesity.
