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

R. J.A. Wanders,J. P.N. Ruiter,D.M. van den Brink,F.M. Vaz,N. van Vlies,J. Gloerich,S. Ferdinandusse

doi:10.1194/jlr.m600050-jlr200

Abstract

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.

Highlights

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 (PPARa)
Our results show that PPARa plays an important role in the regulation of the enzymes involved in phytol degradation
In livers from PPARa2/2 mice, phytol was found to accumulate to much higher levels compared with livers from wild-type animals upon longer duration of the phytol-enriched diet, suggesting a decreased capacity for phytol metabolism in PPARa2/2 mice compared with wild-type animals

Summary

Introduction

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 (PPARa). Addition of phytol to the diet results in an increase of phytol metabolites in tissues and plasma [6, 11,12,13] This has been used as a model to study the effects of the accumulation of phytol metabolites on fatty acid metabolism, in particular via the activation of the nuclear hormone receptor peroxisome proliferator-activated receptor a (PPARa), which is an important transcription factor in the regulation of fatty acid metabolism. Both phytanic and pristanic acid have been shown to activate PPARa in vitro [14, 15], and more recently, PPARa was shown to be activated in vivo in mice fed a phytol-enriched diet [13].

Methods

Results

Conclusion