Metabolism of phytol to phytanic acid in the mouse, and the role of PPAR alpha in its regulation

Phytol, a branched-chain fatty alcohol, is the naturally occurring precursor of phytanic and pristanic acid, branched-chain fatty acids that are both ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor a (PPAR alpha). To investigate the metabolism of phytol and the role of PPAR alpha in its regulation, wild-type and PPAR alpha knockout (PPAR alpha(-/-)) mice were fed a phytol-enriched diet or, for comparison, a diet enriched with Wy-14,643, a synthetic PPAR alpha agonist. After the phytol-enriched diet, phytol could only be detected in small intestine, the site of uptake, and liver. Upon longer duration of the diet, the level of the (E)-isomer of phytol increased significantly in the liver of PPAR alpha(-/-) mice compared with wildtype mice. Activity measurements of the enzymes involved in phytol metabolism showed that treatment with a PPAR alpha agonist resulted in a PPAR alpha-dependent induction of at least two steps of the phytol degradation pathway in liver. Furthermore, the enzymes involved showed a higher activity toward the (E)-isomer than the (Z)-isomer of their respective substrates, indicating a stereospecificity toward the metabolism of (E)-phytol. In conclusion, the results described here show that the conversion of phytol to phytanic acid is regulated via PPARa and is specific for the breakdown of (E)phytol.