MECHANISMS OF REGULATION OF LIVER FATTY-ACID-BINDING PROTEIN

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.