Metabolism of phytol to phytanic acid in the mouse, and the role of PPARalpha 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 alpha (PPARalpha). To investigate the metabolism of phytol and the role of PPARalpha in its regulation, wild-type and PPARalpha knockout (PPARalpha-/-) mice were fed a phytol-enriched diet or, for comparison, a diet enriched with Wy-14,643, a synthetic PPARalpha 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 PPARalpha-/- mice compared with wild-type mice. Activity measurements of the enzymes involved in phytol metabolism showed that treatment with a PPARalpha agonist resulted in a PPARalpha-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 PPARalpha and is specific for the breakdown of (E)-phytol.
Gloerich
J
J
Laboratory of Genetic Metabolic Diseases, Department of Clinical Chemistry, Emma's Children's Hospital, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
van den Brink
D M
DM
Ruiter
J P N
JP
van Vlies
N
N
Vaz
F M
FM
Wanders
R J A
RJ
Ferdinandusse
S
S
D000818:Animals; D006706:Homeostasis; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D020025:Peroxisome Proliferators / Q000494:pharmacology; D010833:Phytic Acid / Q000378:metabolism*; D010836:Phytol / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D010836:Phytol; D010833:Phytic Acid; C006253:pirinixic acid