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

S. Denis,G.A. Jansen,F.M. Vaz,J. Gloerich,N. van Vlies,S. Ferdinandusse,J.P.N. Ruiter,M. Duran,R.J.A. Wanders,M.A. van Werkhoven

doi:10.1194/jlr.m400337-jlr200

Abstract

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

Highlights

Branched-chain fatty acids are ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor ␣ (PPAR␣) in vitro
We studied the expression of both peroxisomal and mitochondrial proteins involved in the metabolism of fatty acids in wild-type and PPAR␣Ϫ/Ϫ mice after phytol feeding
The levels increased with an increasing diet period, but strikingly, the increase was much stronger in wild-type animals than in PPAR␣Ϫ/Ϫ mice

Summary

Introduction

Branched-chain fatty acids (such as phytanic and pristanic acid) are ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor ␣ (PPAR␣) in vitro. To investigate the effects of these physiological compounds in vivo, wild-type and PPAR␣-deficient (PPAR␣؊/؊) mice were fed a phytol-enriched diet. This resulted in increased plasma and liver levels of the phytol metabolites phytanic and pristanic acid. Administration of peroxisome proliferators to rodents results in hepatomegaly and an increase in the Abbreviations: AMACR, ␣-methylacyl-CoA racemase; BB, ␥-butyrobetaine; BBD, ␥-butyrobetaine dioxygenase; BCOX, branched-chain acylCoA oxidase; CAT, carnitine acetyltransferase; COT, carnitine octanoyltransferase; CPT2, carnitine palmitoyltransferase 2; CYP4A1, cytochrome P450 hydroxylase 4A1; DBP, d-bifunctional protein; Elovl, long-chain fatty acid elongase; ESI, electrospray ionization; LBP, l-bifunctional protein; LCAD, long-chain acyl-CoA dehydrogenase; MCAD, mediumchain acyl-CoA dehydrogenase; MTP, mitochondrial trifunctional protein; PhyH, phytanoyl-CoA hydroxylase; PMP70, peroxisomal membrane protein 70; PPAR, peroxisome proliferator-activated receptor; SBCHAD, short branched-chain 3-hydroxyacyl-CoA dehydrogenase; SCAD, shortchain acyl-CoA dehydrogenase; SCHAD, short-chain 3-hydroxyacyl-CoA dehydrogenase; SCOX, straight-chain acyl-CoA oxidase; SCPx, sterol carrier protein x; THIO, peroxisomal 3-ketoacyl-CoA thiolase; TMABADH, trimethylaminobutyraldehyde dehydrogenase; TML, trimethyllysine; VLCAD, very long-chain acyl-CoA dehydrogenase; VLCFA, very long-chain fatty acid

Methods

Results

Conclusion