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 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.