Pristanic acid and phytanic acid: naturally occurring ligands for the nuclear receptor peroxisome proliferater-activated receptor alpha

Phytanic acid and pristanic acid are branched-chain fatty acids, present at micromolar concentrations in the plasma of healthy individuals. Here we sh ow that both phytanic acid and pristanic acid activate the peroxisome proli ferator-activated receptor alpha (PPAR alpha) in a concentration-dependent manner. Activation is observed via the ligand-binding domain of PPAR alpha as well as via a PPAR response element (PPRE). Via the PPRE significant ind uction is found with both phytanic acid and pristanic acid at concentration s of 3 and 1 muM, respectively. The trans-activation of PPAR delta and PPAR gamma by these two ligands is negligible. Besides PPAR alpha, phytanic aci d also trans-activates all three retinoic X receptor subtypes in a concentr ation-dependent manner. In primary human fibroblasts, deficient in phytanic acid alpha -oxidation, trans-activation through PPAR alpha by phytanic aci d is observed. This clearly demonstrates that phytanic acid itself, and not only its metabolite, pristanic acid, is a true physiological ligand for PP AR alpha. Because induction of PPAR alpha occurs at ligand concentrations c omparable to the levels found for phytanic acid and pristanic acid in human plasma, these fatty acids should be seen as naturally occurring ligands fo r PPAR alpha. These results demonstrate that both pristanic acid and phytan ic acid are naturally occurring ligands for PPAR alpha, which are present a t physiological concentrations.