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

Abstract

Branched-chain phytanic acid is metabolized in liver peroxisomes. Sterol carrier protein 2/sterol carrier protein x (SCP2/SCPx) knockout mice, which develop a phenotype with a deficiency in phytanic acid degradation, accumulate 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 induction of liver fatty acid binding protein (L-FABP) expression is observed in comparison to wild-type animals fed standard chow, possibly mediated by the peroxisome proliferator-activated receptor alpha (PPARα). Cytosolic transport of phytanic acid to either peroxisomal membranes or to the nucleus for activation of PPARα may be mediated by L-FABP, which gives rise to the question whether phytanic acid is a transactivator of this protein. 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 expression in liver, which is in the order of that attained with bezafibrate, a known peroxisome proliferator. Finally to test in vitro whether this induction is conferred by phytanic acid, we cotransfected HepG2 cells with an expression plasmid for murine PPARα and a CAT-reporter gene with 176 bp of the murine L-FABP promoter, containing the peroxisome proliferator responsive element (PPRE). After incubation with phytanic acid, we observed a 3.2-fold induction of CAT expression. These findings, both in vivo and in vitro, demonstrate that phytanic acid is a transscriptional activator of L-FABP expression and that this effect is mediated via PPARα.—Wolfrum, C., P. Ellinghaus, M. Fobker, U. Seedorf, G. Assmann, T. Börchers, and F. Spener. Phytanic acid is ligand and transcriptional activator of murine liver fatty acid binding protein. J. Lipid Res. 1999. 40: 708–714.

Keywords

• peroxisome proliferator-activated receptor
• peroxisome proliferation
• sterol carrier protein 2
• sterol carrier protein x
• isothermal titration calorimetry
• SCP2/SCPx-deficient knock out mice