Peroxisome Proliferator-Activated Receptor α/δ/γ Activation Profile by Endogenous Long-Chain Fatty Acids

There is a wealth of information available about endogenous fatty acid ligands for peroxisome proliferator-activated receptor α/δ/γ (PPARα/δ/γ); however, there are few comparative studies of PPARα/δ/γ activation using standardized experimental systems. This study investigated which of 14 major free long-chain fatty acids (LCFAs: C12:0-C22:6) and 15-deoxy-Δ^12,14-prostaglandin J2 (15d-PGJ2) activate PPARα/δ/γ using a coactivator recruitment assay. We recently discovered that eight different synthetic PPAR agonists recruit four different coactivator peptides (PGC1α, CBP, SRC1, TRAP220) with varying potency and efficacy, so we examined the ligand-concentration-dependent recruitment of these four coactivators. All 15 fatty acids (FAs) activated PPARα/δ at high concentrations, but only palmitic acid, stearic acid, oleic acid, and linoleic acid significantly activated PPARα/δ at physiologically relevant concentrations. Lauric acid, myristic acid, palmitic acid, and 15d-PGJ2 activated PPARγ at high concentrations, but only palmitic acid slightly activated PPARγ at physiologically relevant concentrations. FA ligands exhibited different coactivator preference compared to synthetic PPAR agonists, including approved drugs such as pemafibrate, seladelpar, and pioglitazone, suggesting that these agonists may regulate target gene transcription in a different manner than natural FA ligands. Such differences may be relevant to the pathogenesis of side effects of synthetic PPAR agonists occasionally observed in (pre)clinical studies.