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J. Lipid Res.
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Journal of Lipid Research, Vol. 41, 1801-1807, November 2000
Copyright © 2000 by Lipid Research, Inc.

Original Article

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

Anna W. M. Zomera,b, Bart van der Burga, Gerbert A. Jansenc, Ronald J. A. Wandersc,d, Bwee Tien Poll-Theb, and Paul T. van der Saaga
a Hubrecht Laboratory, Netherlands Institute for Developmental Biology, 3584 CT Utrecht, The Netherlands
b Department of Pediatrics/Metabolic Diseases, University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands
c Departments of Pediatrics, Laboratory for Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands
d (Emma Children's Hospital) and Clinical Chemistry, Laboratory for Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands

Correspondence to: Anna W. M. Zomer

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 {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 induction is found with both phytanic acid and pristanic acid at concentrations of 3 and 1 µM, respectively. The trans-activation of PPAR{delta} and PPAR{gamma} by these two ligands is negligible. Besides PPAR{alpha}, phytanic acid also trans-activates all three retinoic X receptor subtypes in a concentration-dependent manner. In primary human fibroblasts, deficient in phytanic acid {alpha}-oxidation, trans-activation through PPAR{alpha} 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 PPAR{alpha}. Because induction of PPAR{alpha} 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{alpha}.

These results demonstrate that both pristanic acid and phytanic acid are naturally occurring ligands for PPAR{alpha}, 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 {alpha}. J. Lipid Res. 2000. 41: 1801;–1807.

Supplementary key words: natural ligand, peroxisomal disorder, retinoic X receptor, phytol derivatives


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