Abstract
Phytanic acid and pristanic acid are branched-chain fatty acids, present at micromolar concentrations in the plasma of healthy individuals. Here we show that both phytanic acid and pristanic acid activate the peroxisome proliferator-activated receptor α (PPARα) in a concentration-dependent manner. Activation is observed via the ligand-binding domain of PPARα as well as via a PPAR response element (PPRE). Via the PPRE significant induction is found with both phytanic acid and pristanic acid at concentrations of 3 and 1 μM, respectively. The trans-activation of PPARδ and PPARγ by these two ligands is negligible. Besides PPARα, phytanic acid also trans-activates all three retinoic X receptor subtypes in a concentration-dependent manner. In primary human fibroblasts, deficient in phytanic acid α-oxidation, trans-activation through PPARα by phytanic acid is observed. This clearly demonstrates that phytanic acid itself, and not only its metabolite, pristanic acid, is a true physiological ligand for PPARα. Because induction of PPARα occurs at ligand concentrations comparable to the levels found for phytanic acid and pristanic acid in human plasma, these fatty acids should be seen as naturally occurring ligands for PPARα. These results demonstrate that both pristanic acid and phytanic acid are naturally occurring ligands for PPARα, which are present at physiological concentrations.—Zomer, A. W. M., B. van der Burg, G. A. Jansen, R. J. A. Wanders, B. T. Poll-The, and P. T. van der Saag. Pristanic acid and phytanic acid: naturally occurring ligands for the nuclear receptor peroxisome proliferator-activated receptor α. J. Lipid Res. 2000. 41: 1801–1807.
Highlights
Phytanic acid and pristanic acid are branchedchain fatty acids, present at micromolar concentrations in the plasma of healthy individuals
Microorganisms, which are present in the Abbreviations: EC50, median effective concentration; FCS, fetal calf serum; LBD, ligand-binding domain; PhyH, phytanoyl-CoA hydroxylase; Peroxisome proliferator-activated receptors (PPARs), peroxisome proliferator-activated receptor; peroxisome-targeting signal type 2 (PTS2), peroxisometargeting signal type 2; PPRE, PPAR response element; retinoid X receptor (RXR), retinoid
PPAR␣ is activated by a variety of natural and synthetic ligands such as various long-chain fatty acids, eicosanoids (leukotriene B4 and 8(S)-hydroxyeicosatetraenoic acid), and hypolipidemic drugs
Summary
Phytanic acid and pristanic acid are branchedchain fatty acids, present at micromolar concentrations in the plasma of healthy individuals. Deficient in phytanic acid ␣-oxidation, trans-activation through PPAR␣ by phytanic acid is observed. This clearly demonstrates that phytanic acid itself, and its metabolite, pristanic acid, is a true physiological ligand for PPAR␣. Because induction of PPAR␣ occurs at ligand concentrations comparable to the levels found for phytanic acid and pristanic acid in human plasma, these fatty acids should be seen as naturally occurring ligands for PPAR␣. Microorganisms, which are present in the Abbreviations: EC50, median effective concentration; FCS, fetal calf serum; LBD, ligand-binding domain; PhyH, phytanoyl-CoA hydroxylase; PPAR, peroxisome proliferator-activated receptor; PTS2, peroxisometargeting signal type 2; PPRE, PPAR response element; RXR, retinoid. Besides heterodimerization with various members of the nuclear hormone receptor family such as PPAR and retinoic acid receptor, RXRs can homodimerize and regulate trans-activation of target genes
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