title: Fatty-acyl-CoA thioesters inhibit recruitment of steroid receptor co-activator 1 to alpha and gamma isoforms of peroxisome-proliferator-activated receptors by competing with agonists.
abstract: Peroxisome-proliferator-activated receptors (PPARs) alpha and gamma are ligand-dependent transcription factors that are key regulators of lipid and carbohydrate homoeostasis. Fatty acids bind to the ligand-binding domains (LBDs) of PPARalpha and PPARgamma and activate these receptors. To clarify whether fatty-acyl-CoAs interact directly with the LBDs of PPARalpha and PPARgamma, we performed a competition binding assay with radiolabelled KRP-297, a known dual agonist for these receptors. We show here that fatty-acyl-CoAs bind directly to PPARalpha and PPARgamma. Interestingly, fatty-acyl-CoAs, unlike fatty acids, failed to recruit steroid receptor co-activator 1 (SRC-1), on the basis of conformational changes in the LBDs of PPARalpha and PPARgamma. Moreover, fatty-acyl-CoAs also markedly inhibited agonist-induced recruitment of SRC-1. These findings demonstrate that fatty-acyl-CoAs have a novel function in the signalling pathways of PPARalpha and PPARgamma.
authors.affiliation: Central Research Laboratories, Kyorin Pharmaceutical Co., Ltd, 2399-1 Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan. kouji.murakami@mb2.kyorin-pharm.co.jp
authors.forename: K
authors.initials: K
authors.lastname: Murakami
authors.forename: T
authors.initials: T
authors.lastname: Ide
authors.forename: T
authors.initials: T
authors.lastname: Nakazawa
authors.forename: T
authors.initials: T
authors.lastname: Okazaki
authors.forename: T
authors.initials: T
authors.lastname: Mochizuki
authors.forename: T
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000214:Acyl Coenzyme A / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D005227:Fatty Acids / Q000494:pharmacology; D051548:Histone Acetyltransferases; D008024:Ligands; D008099:Liver / Q000201:enzymology; D008297:Male; D009132:Muscles / Q000201:enzymology; D056920:Nuclear Receptor Coactivator 1; D010957:Plasmids; D020033:Protein Isoforms / Q000819:agonists / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D014316:Tritium
chemical_list: D000214:Acyl Coenzyme A; D005227:Fatty Acids; D008024:Ligands; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D053778:Thiazolidines; D014157:Transcription Factors; D014316:Tritium; C116017:5-((2,4-dioxo-5-thiazolidinyl)methyl)-2-methoxy-N-((4-(trifluoromethyl)phenyl)methyl)benzamide; D051548:Histone Acetyltransferases; D056920:Nuclear Receptor Coactivator 1