Phytanic acid activates the peroxisome proliferator-activated receptor α (PPARα) in sterol carrier protein 2- sterol carrier protein x-deficient mice

We showed recently that a targeted null mutation in the murine sterol carrier protein 2-/sterol carrier protein x-gene (Scp2) leads to defective peroxisomal catabolism of 3,7,11,15-tetramethylhexadecanoic acid (phytanic acid), peroxisome proliferation, hypolipidemia, and enhanced hepatic expression of several genes that have been demonstrated to be transcriptionally regulated by the peroxisome proliferator-activated receptor alpha (PPAR alpha), As a broad range of fatty acids activates PPAR alpha in vitro, we examined whether the latter effects could be because of phytanic acid-induced activation of this transcription factor. Dietary phytol supplementation was used to modulate the concentration of phytanic acid in C57B1/6 and Scp2 (-/-) mice. We found that the serum concentrations of phytanic acid correlated well with the expression of genes encoding peroxisomal beta-oxidation enzymes and liver fatty acid-binding protein, who have all been demonstrated to contain functionally active peroxisome proliferator response elements in their promoter regions. In accordance with these findings, a stimulating effect on acyl-CoA oxidase gene expression was also observed after incubation of the rat hepatoma cell line MH1C1 with phytanic acid. Moreover, reporter gene studies revealed that phytanic acid induces the expression of a peroxisome proliferator response element-driven chloramphenicol transferase reporter gene comparable with strong peroxisome proliferators, In addition, the ability of phytanic acid to act as an inductor of PPAR alpha-dependent gene expression corresponded with high affinity binding of this dietary branched chain fatty acid to recombinant PPAR alpha, We conclude that phytanic acid can be considered as a bona fide physiological ligand of murine PPAR alpha.