NUCLEAR RECEPTORS Partners in Metabolic Regulation

The estrogen-related receptor α proteins (ERRs) are nuclear hormone receptor-like proteins that have been implicated in control of lipid and energy metabolism. Although similar in structure to estrogen receptors, ERRs have no known endogenous ligand and appear to be constitutively active, promoting gene transcription with certain coactivator proteins. One such coactivator that interacts with ERRα is peroxisome proliferator-activated receptor (PPAR) coactivator 1α (PGC-1α), also a critical metabolic regulator. Willy et al. screened synthetic compounds to identify an inhibitor (more properly an inverse agonist) of ERRα. They also used transcriptional array analysis to identify monoamine oxidase B as a transcriptional target of ERRα in a human breast cancer cell line. Reporter assays in transfected cells and analysis of MAOB gene expression in cells infected with a retrovirus encoding PGC-1α showed that ERRα and PGC-1α cooperate to stimulate expression of MAOB mRNA. The authors used the new inhibitor to show that effects of PGC-1α were dependent on ERRα. Thus metabolic regulation appears to rely on a close cooperation between ERRα and PGC-1α in which ERRα likely regulates its own expression through interaction with PGC-1α and PGC-1α stimulates expression of ERRα, a factor that then functions with PGC-1α to coordinately regulate expression of target genes.

P. J. Willy, I. R. Murray, J. Qian, B. B. Busch, W. C. Stevens Jr., R. Martin, R. Mohan, S. Zhou, P. Ordentlich, P. Wei, D. W. Sapp, R. A. Horlick, R. A. Heyman, I. G. Schulman, Regulation of PPAR coactivator 1 (PGC-1) signaling by an estrogen-related receptor α (ERRα) ligand. Proc. Natl. Acad. Sci. U.S.A. 101, 8912-8917 (2004). [Abstract] [Full Text]