Phytanic acid activates the peroxisome proliferator-activated receptor alpha (PPAR alpha) in sterol carrier protein 2-/ sterol carrier protein x-deficient mice

We showed recently that a targeted null mutation in the murine sterol carri er protein 2-/sterol carrier protein x-gene (Scp2) leads to defective perox isomal 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 regula ted by the peroxisome proliferator-activated receptor alpha (PPAR alpha), A s a broad range of fatty acids activates PPAR alpha in vitro, we examined w hether the latter effects could be because of phytanic acid-induced activat ion of this transcription factor. Dietary phytol supplementation was used t o modulate the concentration of phytanic acid in C57B1/6 and Scp2 (-/-) mic e. We found that the serum concentrations of phytanic acid correlated well with the expression of genes encoding peroxisomal beta-oxidation enzymes an d liver fatty acid-binding protein, who have all been demonstrated to conta in functionally active peroxisome proliferator response elements in their p romoter 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 s tudies revealed that phytanic acid induces the expression of a peroxisome p roliferator response element-driven chloramphenicol transferase reporter ge ne comparable with strong peroxisome proliferators, In addition, the abilit y of phytanic acid to act as an inductor of PPAR alpha-dependent gene expre ssion corresponded with high affinity binding of this dietary branched chai n fatty acid to recombinant PPAR alpha, We conclude that phytanic acid can be considered as a bona fide physiological ligand of murine PPAR alpha.