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

Abstract

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

Keywords

• peroxisome proliferator-activated receptor α
• peroxisomes
• mitochondria
• fatty acid β-oxidation
• very long-chain fatty acids
• branched-chain fatty acids