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

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