Liver fatty acid-binding protein (L-FABP) expression is modulated by d
evelopmental, hormonal, dietary, and pharmacological factors. The most
pronounced induction is seen after treatment with peroxisome prolifer
ators, which induce L-FABP coordinately with microsomal cytochrome P-4
50 4A1 and the enzymes of peroxisomal fatty acid beta-oxidation. These
effects of peroxisome proliferators may be mediated by a receptor whi
ch has been shown to be activated by peroxisome proliferators in mamma
lian cell transfection studies. However, the peroxisome proliferators
tested thus far do not bind to this receptor, known as the peroxisome
proliferator-activated receptor (PPAR), and its endogenous ligand(s) a
lso remain unknown. Peroxisome proliferators inhibit mitochondrial bet
a-oxidation, and one hypothesis is that the dicarboxylic fatty acid me
tabolites of accumulated LCFA, formed via the P-450 4A1 omegaBAR-oxida
tion pathway, serve as primary inducers of L-FABP and peroxisomal beta
-oxidation. We have tested this hypothesis in primary hepatocyte cultu
res exposed to clofibrate (CF). Inhibition of P-450 4A1 markedly dimin
ished, via a pre-translational mechanism, the CF induction of L-FABP a
nd peroxisomal beta-oxidation. In further experiments, long-chain dica
rboxylic acids, the final products of the P-450 4A1 omegaBAR-oxidation
pathway, but not LCFA, induced L-FABP and peroxisomal beta-oxidation
pre-translationally. These results suggest a role, in part, for long-c
hain dicarboxylic acids in mediating the peroxisome proliferator induc
tion of L-FABP and peroxisomal beta-oxidation. We also found that LCFA
, which undergo rapid hepatocellular metabolism, could become inducers
of L-FABP and peroxisomal beta-oxidation under conditions where their
metabolism was inhibited. The role of the PPAR in mediating these eff
ects is unknown, but clearly warrants further study. The induction of
L-FABP and peroxisomal beta-oxidation by LCFA and/or their omegaBAR-ox
idized metabolites may provide a means for limiting the deleterious ef
fects of increased intracellular concentrations of free LCFA, and thus
act as an important hepatocellular adaptation to impairment or overlo
ad of mitochondrial LCFA oxidation.