Phytanic acid is ligand and transcriptional activator of murine liver fatty acid binding protein.
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.
Wolfrum
C
C
Institut für Biochemie, D-48149 Münster, Germany.
Ellinghaus
P
P
Fobker
M
M
Seedorf
U
U
Assmann
G
G
Börchers
T
T
Spener
F
F
D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D018076:DNA, Complementary; D004926:Escherichia coli / Q000235:genetics; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D015870:Gene Expression / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D051379:Mice; D018996:Myelin P2 Protein / Q000235:genetics* / Q000378:metabolism*; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010831:Phytanic Acid / Q000378:metabolism* / Q000494:pharmacology*; D010836:Phytol / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation; D014162:Transfection
D002352:Carrier Proteins; D018076:DNA, Complementary; C493320:Fabp1 protein, mouse; C493321:Fabp1 protein, rat; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D000960:Hypolipidemic Agents; D018996:Myelin P2 Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014157:Transcription Factors; D010831:Phytanic Acid; D010836:Phytol; D015500:Chloramphenicol O-Acetyltransferase; D001629:Bezafibrate