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J. Lipid Res.
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A more recent version of this article appeared on April 1, 2005

Papers In Press, published online ahead of print January 16, 2005
J. Lipid Res., doi:10.1194/jlr.M400337-JLR200
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Submitted on September 7, 2004
Revised on December 16, 2004
Accepted on January 4, 2005

A phytol-enriched diet induces changes in fatty acid metabolism in mice both via PPARalpha -dependent and independent pathways

Jolein Gloerich, Naomi van Vlies, Gerbert A. Jansen, Simone Denis, Jos P. N. Ruiter, Michiel A. van Werkhoven, Marinus Duran, Frédéric M. Vaz, Ronald J. A. Wanders, and Sacha Ferdinandusse

Lab. Genetic Metabolic Diseases, Academic Medical Center, Amsterdam 1100 DE

Corresponding Author: s.ferdinandusse{at}amc.uva.nl

Branched-chain fatty acids (like phytanic and pristanic acid) are ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARalpha ) in vitro. To investigate the effects of these physiological compounds in vivo, wild type and PPARalpha -/- mice were fed a phytol-enriched diet. This resulted in elevated plasma and liver levels of the phytol metabolites phytanic and pristanic acid. In wild type mice plasma fatty acid levels decreased after phytol feeding, whereas in PPARalpha -/- mice the already elevated fatty acid levels increased. In addition, PPARalpha -/- mice were found to be carnitine-deficient in both plasma and liver. Dietary phytol increased liver free carnitine in wild type animals, but not in PPARalpha -/- mice. Investigation of carnitine biosynthesis revealed that PPARalpha is likely involved in the regulation of carnitine homeostasis. Furthermore, phytol feeding resulted in a PPARalpha -dependent induction of various peroxisomal and mitochondrial beta -oxidation enzymes. In addition, a PPARalpha -independent induction of catalase, phytanoyl-CoA hydroxylase, carnitine octanoyltransferase, peroxisomal 3-ketoacyl-CoA thiolase and straight-chain acyl-CoA oxidase was observed. In conclusion, branched-chain fatty acids are physiologically relevant ligands of PPARalpha in mice. These findings are especially relevant for disorders where branched-chain fatty acids accumulate, such as Refsum disease and peroxisome biogenesis disorders.


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