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

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 whe...

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Bibliographic Details
Published in:Biochemical journal 2001-01, Vol.353 (Pt 2), p.231-238
Main Authors: Murakami, K, Ide, T, Nakazawa, T, Okazaki, T, Mochizuki, T, Kadowaki, T
Format: Article
Language:English
Subjects:
Acyl Coenzyme A - antagonists & inhibitors
Acyl Coenzyme A - metabolism
Acyl Coenzyme A - pharmacology
Animals
Binding, Competitive - drug effects
Fatty Acids - pharmacology
Histone Acetyltransferases
Ligands
Liver - enzymology
Male
Muscles - enzymology
Nuclear Receptor Coactivator 1
Plasmids
Protein Isoforms - agonists
Protein Isoforms - metabolism
Rats
Rats, Zucker
Receptors, Cytoplasmic and Nuclear - agonists
Receptors, Cytoplasmic and Nuclear - metabolism
Signal Transduction
Thiazoles - pharmacology
Thiazolidines
Transcription Factors - agonists
Transcription Factors - metabolism
Tritium
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Summary: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.
ISSN:0264-6021
1470-8728
DOI:10.1042/0264-6021:3530231