Phytanic acid is ligand and transcriptional activator of murine liver fatty acid binding protein

Branched-chain phytanic acid is metabolized in liver peroxisomes, Sterol ca rrier protein 2/sterol carrier protein x (SCP2/SCPx) knockout mice, which d evelop a phenotype with a deficiency in phytanic acid degradation, accumula te dramatically high concentrations of this fatty acid in serum (Seedorf at al, 1998. Genes Dev. 12: 1189-1201) and liver, Concomitantly, a 6.9-fold i nduction of liver fatty acid binding protein (L-FABP) expression is observe d in comparison to wild-type animals fed standard chow, possibly mediated b y the peroxisome proliferator-activated receptor alpha (PPAR alpha), Cytoso lic transport of phytanic acid to either peroxisomal membranes or to the nu cleus for activation of PPAR alpha may be mediated by L-FABP, which gives r ise to the question whether phytanic acid is a transactivator of this prote in, Here we show first that phytanic acid binds to recombinant L-FABP with high affinity, Then the increase of the in vivo phytanic acid concentration by phytol feeding to mice results in a 4-fold induction of L-FABP expressi on in Liver, which is in the order of that attained with bezafibrate, a kno wn peroxisome proliferator. Finally to test in vitro whether this induction is conferred by phytanic acid, we cotransfected HepG2 cells with an expres sion plasmid for murine PPAR alpha and a CAT-reporter gene with 176 bp of t he murine L-FABP promoter, containing the peroxisome proliferator responsiv e element (PPRE), After incubation with phytanic acid, we observed a 3.2-fo ld induction of CAT expression. These findings, both in vivo and in vitro, demonstrate that phytanic acid is a transcriptional activator of L-FABP exp ression and that this effect is mediated via PPAR alpha.