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Journal of Lipid Research, Vol. 46, 716-726, April 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

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

J. Gloerich, N. van Vlies, G. A. Jansen, S. Denis, J. P. N. Ruiter, M. A. van Werkhoven, M. Duran, F. M. Vaz, R. J. A. Wanders and S. Ferdinandusse¹

University of Amsterdam, Academic Medical Center, Departments of Clinical Chemistry and Pediatrics, Laboratory for Genetic Metabolic Diseases, 1100 DE Amsterdam, The Netherlands

¹ To whom correspondence should be addressed. e-mail: s.ferdinandusse{at}amc.uva.nl

Branched-chain fatty acids (such as phytanic and pristanic acid) are ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) in vitro. To investigate the effects of these physiological compounds in vivo, wild-type and PPAR-deficient (PPAR^–/–) mice were fed a phytol-enriched diet. This resulted in increased 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 PPAR^–/– mice, the already elevated fatty acid levels increased. In addition, PPAR^–/– 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 PPAR^–/– mice. Investigation of carnitine biosynthesis revealed that PPAR is likely involved in the regulation of carnitine homeostasis. Furthermore, phytol feeding resulted in a PPAR-dependent induction of various peroxisomal and mitochondrial ß-oxidation enzymes. In addition, a PPAR-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 PPAR in mice. These findings are especially relevant for disorders in which branched-chain fatty acids accumulate, such as Refsum disease and peroxisome biogenesis disorders.

Abbreviations: AMACR, -methylacyl-CoA racemase; BB, -butyrobetaine; BBD, -butyrobetaine dioxygenase; BCOX, branched-chain acyl-CoA oxidase; CAT, carnitine acetyltransferase; COT, carnitine octanoyltransferase; CPT2, carnitine palmitoyltransferase 2; CYP4A1, cytochrome P450 hydroxylase 4A1; DBP, D-bifunctional protein; Elovl, long-chain fatty acid elongase; ESI, electrospray ionization; LBP, L-bifunctional protein; LCAD, long-chain acyl-CoA dehydrogenase; MCAD, medium-chain acyl-CoA dehydrogenase; MTP, mitochondrial trifunctional protein; PhyH, phytanoyl-CoA hydroxylase; PMP70, peroxisomal membrane protein 70; PPAR, peroxisome proliferator-activated receptor; SBCHAD, short branched-chain 3-hydroxyacyl-CoA dehydrogenase; SCAD, short-chain acyl-CoA dehydrogenase; SCHAD, short-chain 3-hydroxyacyl-CoA dehydrogenase; SCOX, straight-chain acyl-CoA oxidase; SCPx, sterol carrier protein x; THIO, peroxisomal 3-ketoacyl-CoA thiolase; TMABADH, trimethylaminobutyraldehyde dehydrogenase; TML, trimethyllysine; VLCAD, very long-chain acyl-CoA dehydrogenase; VLCFA, very long-chain fatty acid

Supplementary key words peroxisome proliferator-activated receptor • peroxisomes • mitochondria • fatty acid ß-oxidation • very long-chain fatty acids • branched-chain fatty acids • acylcarnitines • peroxisomal disorders

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