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

J Lipid Res. 1999 Apr;40(4):708-14.

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 (PPARalpha). Cytosolic transport of phytanic acid to either peroxisomal membranes or to the nucleus for activation of PPARalpha 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 PPARalpha 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 transcriptional activator of L-FABP expression and that this effect is mediated via PPARalpha.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bezafibrate / pharmacology
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Cell Line
  • Chloramphenicol O-Acetyltransferase / genetics
  • DNA, Complementary
  • Escherichia coli / genetics
  • Fatty Acid-Binding Protein 7
  • Fatty Acid-Binding Proteins
  • Gene Expression / drug effects
  • Hypolipidemic Agents / pharmacology
  • Liver / metabolism
  • Mice
  • Myelin P2 Protein / genetics*
  • Myelin P2 Protein / metabolism*
  • Neoplasm Proteins*
  • Nerve Tissue Proteins*
  • Phytanic Acid / metabolism*
  • Phytanic Acid / pharmacology*
  • Phytol / pharmacology
  • Rats
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Recombinant Proteins / metabolism
  • Transcription Factors / genetics
  • Transcription, Genetic / drug effects*
  • Transcriptional Activation
  • Transfection

Substances

  • Carrier Proteins
  • DNA, Complementary
  • Fabp1 protein, mouse
  • Fabp1 protein, rat
  • Fabp5 protein, mouse
  • Fabp7 protein, mouse
  • Fabp7 protein, rat
  • Fatty Acid-Binding Protein 7
  • Fatty Acid-Binding Proteins
  • Hypolipidemic Agents
  • Myelin P2 Protein
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Recombinant Proteins
  • Transcription Factors
  • Phytanic Acid
  • Phytol
  • Chloramphenicol O-Acetyltransferase
  • Bezafibrate

Associated data

  • GENBANK/Y14660