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 lig and-dependent transcription factors that are key regulators of lipid and ca rbohydrate homoeostasis. Fatty acids bind to the ligand-binding domains (LB Ds) of PPAR alpha and PPAR gamma and activate these receptors. To clarify w hether fatty-acyl-CoAs interact directly with the LBDs of PPAR alpha and PP AR gamma, we performed a competition binding assay with radiolabelled KRP-2 97, a known dual agonist for these receptors. We show here that fatty-acyl- CoAs bind directly to PPAR alpha. and PPAR gamma. 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 PPAR alpha and PPAR gamma. Moreover, fatty-acyl-CoAs also markedly inhibited agonist- induced recruitment of SRC-1. These findings demonstrate that fatty-acyl Co As have a novel function in the signalling pathways of PPAR alpha and PPAR gamma.