title: 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.affiliation: Department of Biology, X-Ceptor Therapeutics, Inc., San Diego, CA 92121, USA. pwilly@x-ceptor.com
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Willy
authors.forename: Ian R
authors.initials: IR
authors.lastname: Murray
authors.forename: Jing
authors.initials: J
authors.lastname: Qian
authors.forename: Brett B
authors.initials: BB
authors.lastname: Busch
authors.forename: William C
authors.initials: WC
authors.lastname: Stevens
authors.forename: Richard
authors.initials: R
authors.lastname: Martin
authors.forename: Raju
authors.initials: R
authors.lastname: Mohan
authors.forename: Sihong
authors.initials: S
authors.lastname: Zhou
authors.forename: Peter
authors.initials: P
authors.lastname: Ordentlich
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Sapp
authors.forename: Robert A
authors.initials: RA
authors.lastname: Horlick
authors.forename: Richard A
authors.initials: RA
authors.lastname: Heyman
authors.forename: Ira G
authors.initials: IG
authors.lastname: Schulman
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005454:Fluorescence Polarization; D015870:Gene Expression; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D008995:Monoamine Oxidase / Q000096:biosynthesis / Q000235:genetics; D009154:Mutation; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011960:Receptors, Estrogen / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014162:Transfection; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D006360:Heat-Shock Proteins; D008024:Ligands; D008995:Monoamine Oxidase; D009570:Nitriles; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D013844:Thiazoles; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C486497:PPARGC1A protein, human; C488234:XCT790