Phytanoyl-CoA hydroxylase activity is induced by phytanic acid

Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid present in various dietary products such as milk, cheese and fis h. In patients with Refsum disease, accumulation of phytanic acid occurs du e to a deficiency of phytanoyl-CoA hydroxylase, a peroxisomal enzyme contai ning a peroxisomal targeting signal 2. Recently, phytanoyl-CoA hydroxylase cDNA has been isolated and functional mutations have been identified. As it has been shown that phytanic acid activates the nuclear hormone receptors peroxisome proliferator-activated receptor (PPAR)alpha and all three retino id X receptors (RXRs), the intracellular concentration of this fatty acid s hould be tightly regulated. When various cell lines were grown in the presence of phytanic acid, the ac tivity of phytanoyl-CoA hydroxylase increased up to four times, depending o n the particular cell type. In one cell line, HepG2, no induction of phytan oyl-CoA hydroxylase activity was observed. After addition of phytanic acid to COS-1 cells, an increase in phytanoyl-CoA hydroxylase activity was obser ved within 2 h, indicating a quick cell response. No stimulation of phytano yl-CoA hydroxylase was observed when COS-1 cells were grown in the presence of clofibric acid, 9-cis-retinoic acid or both ligands together. This indi cates that the activation of phytanoyl-CoA hydroxylase is not regulated via PPAR alpha or RXR. However, stimulation of PPAR alpha and all RXRs by clof ibric acid and 9-cis-retinoic acid was observed in transient transfection a ssays. These results suggest that the induction of phytanoyl-CoA hydroxylas e by phytanic acid does not proceed via one of the nuclear hormone receptor s, RXR or PPAR alpha.