Abstract
Both the enzymes of peroxisomal fatty acid beta-oxidation and the liver fatty acid-binding protein (L-FABP) are induced in the liver by peroxisome proliferators, such as clofibrate (CF), as well as high fat diets. One proposed mechanism for this induction is that it represents an adaptive response to altered intracellular fatty acid fluxes, mediated by dicarboxylic fatty acids formed via the cytochrome P-450IVA1 omega-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 not P-450IVA1, could be significantly inhibited pretranslationally by concurrent exposure of cultured hepatocytes to inactivators of cytochromes P-450, such as 1-aminobenzotriazole and 10-undecynoic acid. Hexadecanedioic acid, a 16-carbon dicarboxylic fatty acid, that is poorly metabolized in hepatocytes, induced peroxisomal beta-oxidation and L-FABP, but not P-450IVA1, via a pretranslational mechanism that was not inhibited by 1-aminobenzotriazole. Long-chain monocarboxylic acids were without such inducing effect. In further studies, non-beta-oxidizable dicarboxylic acid analogs were found to display greater potency as inducers of peroxisomal beta-oxidation when compared to hexadecanedioic acid. The inducing effects of the dicarboxylic acid analogs were also independent of the P-450 omega-oxidation pathway. The results of these studies suggest that the regulation of peroxisomal beta-oxidation enzymes and L-FABP is mediated, to a significant extent, by poorly metabolized long-chain dicarboxylic acids formed via the P-450IVA1 pathway.
Highlights
From the Departmentsof SMedicine and lfPhrmaceutica1 Chemistry and the §Liver Center, UniversoiftyCalifornia, S a n Francis& California 94143-0538
P-450IVA1 w-oxidation pathway plays an important role in shown to be the case in cultured hepatocytes, with the CF
The induction by peroxisome proliferators of peroxisomal @- mediatedincreasein P-450IVA1 activityoccurringearlier, Regulation of PeroPxi-sOomxainaddlation and togreater magnitude, than the increase in either peroxi- ther support to the hypothesis that the P-45OIVA1 w-oxidasomal 0-oxidation or liverfatty acid-binding protein (L-FABP) (Fig. 1).The time course of tion pathway plays an important role in the peroxisome induction of P-450IVA1 vis a vis peroxisomal @-oxidationhas proliferator induction of peroxisomal @-oxidation and L
Summary
From the Departmentsof SMedicine and lfPhrmaceutica1 Chemistry and the §Liver Center, UniversoiftyCalifornia, S a n Francis& California 94143-0538. If long-chain dicarboxylic fatty acids are the proximate effectors of the induction of peroxisomal @-oxidation Poor internalization of dicarboxylic fatty acids into hepatoand L-FABP, theirinducing effects should be independ- cytes from the culture medium was considered a factor that ent of the P-450IVA1pathway and not be inhibited by ABT.
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