INDUCTION OF PEROXISOMAL FATTY-ACID BETA-OXIDATION AND LIVER FATTY ACID-BINDING PROTEIN BY PEROXISOME PROLIFERATORS - MEDIATION VIA THE CYTOCHROME P-450IVA1 OMEGA-HYDROXYLASE PATHWAY

Both the enzymes of peroxisomal fatty acid beta-oxidation and the live r fatty acid-binding protein (L-FABP) are induced in the liver by pero xisome proliferators, such as clofibrate (CF), as well as high fat die ts. One proposed mechanism for this induction is that it represents an adaptive response to altered intracellular fatty acid fluxes, mediate d by dicarboxylic fatty acids formed via the cytochrome P-450IVA1 omeg a-oxidation pathway. The studies presented in this paper were designed to investigate the role of the products of P-450IVA1 omega-oxidation in the regulation of peroxisomal beta-oxidation and L-FABP. In primary hepatocyte cultures exposed to CF, the increase in P-450IVA1 activity preceded the induction of peroxisomal beta-oxidation and L-FABP. The CF-mediated increases in peroxisomal beta-oxidation and L-FABP, but no t P-450IVA1, could be significantly inhibited pretranslationally by co ncurrent exposure of cultured hepatocytes to inactivators of cytochrom es P-450, such as 1-aminobenzotriazole and 10-undecynoic acid. Hexadec anedioic acid, a 16-carbon dicarboxylic fatty acid, that is poorly met abolized in hepatocytes, induced peroxisomal beta-oxidation and L-FABP , but not P-450IVA1, via a pretranslational mechanism that was not inh ibited by 1-aminobenzotriazole. Long-chain monocarboxylic acids were w ithout such inducing effect. In further studies, non-beta-oxidizable d icarboxylic acid analogs were found to display greater potency as indu cers of peroxisomal beta-oxidation when compared to hexadecanedioic ac id. The inducing effects of the dicarboxylic acid analogs were also in dependent of the P-450 omega-oxidation pathway. The results of these s tudies suggest that the regulation of peroxisomal beta-oxidation enzym es and L-FABP is mediated, to a significant extent, by poorly metaboli zed long-chain dicarboxylic acids formed via the P-450IVA1 pathway.