Regulation of PPARgamma coactivator 1alpha (PGC-1alpha) signaling by an estrogen-related receptor alpha (ERRalpha) ligand.

Abstract

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.

• Authors: Patricia J Willy, Ian R Murray, Jing Qian, Brett B Busch, William C Stevens Jr, Richard Martin, Raju Mohan, Sihong Zhou, Peter Ordentlich, Ping Wei, Douglas W Sapp, Robert A Horlick, Richard A Heyman, Ira G Schulman
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 101 Issue 24 Pg. 8912-7 (Jun 15 2004) ISSN: 0027-8424 [Print] United States
• PMID: 15184675 (Publication Type: Journal Article)

Chemical References

• Heat-Shock Proteins
• Ligands
• Nitriles
• PPARGC1A protein, human
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Receptors, Cytoplasmic and Nuclear
• Receptors, Estrogen
• Recombinant Proteins
• Thiazoles
• Transcription Factors
• XCT790
• Monoamine Oxidase

Topics

• Animals
• Base Sequence
• Cell Line
• Cell Line, Tumor
• Chlorocebus aethiops
• Fluorescence Polarization
• Gene Expression
• HeLa Cells
• Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Ligands
• Mice
• Molecular Sequence Data
• Monoamine Oxidase (biosynthesis, genetics)
• Mutation
• Nitriles (chemistry, pharmacology)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Promoter Regions, Genetic (genetics)
• Receptors, Cytoplasmic and Nuclear (agonists, genetics, metabolism, physiology)
• Receptors, Estrogen (agonists, genetics, metabolism, physiology)
• Recombinant Proteins (agonists, genetics, metabolism)
• Signal Transduction
• Thiazoles (chemistry, pharmacology)
• Transcription Factors (antagonists & inhibitors, metabolism)
• Transfection
• ERRalpha Estrogen-Related Receptor