REGULATION OF PATHWAYS OF EXTRAMITOCHONDRIAL FATTY-ACID OXIDATION ANDLIVER FATTY-ACID-BINDING PROTEIN BY LONG-CHAIN MONOCARBOXYLIC FATTY-ACIDS IN HEPATOCYTES - EFFECT OF INHIBITION OF CARNITINE PALMITOYLTRANSFERASE-I

The regulation of the extramitochondrial fatty acid oxidation pathways located in the peroxisomes and the endoplasmic reticulum is not fully understood. Although both long-chain dicarboxylic fatty acids, which are poorly metabolized in hepatocytes, and non-beta-oxidizable fatty a cid analogs induce peroxisomal beta-oxidation and liver fatty acid-bin ding protein (L-FABP) by a pretranslational mechanism, monocarboxylic long-chain fatty acids, which are rapidly esterified and oxidized, do not. To establish whether impaired utilization and, hence, sustained i ntracellular levels of monocarboxylic long-chain fatty acids increase their efficacy as inducers, the effect of oleic acid on cytochrome P-4 50 4A1, peroxisomal beta-oxidation, and L-FABP during inhibition of mi tochondrial beta-oxidation was determined. In primary hepatocyte cultu res, oleic acid had no inducing effect, but in the presence of 2-tetra decylglycidic acid (TDGA), an inhibitor of carnitine palmitoyltransfer ase I, it induced P-450 4A1, peroxisomal beta-oxidation, and L-FABP pr etranslationally. An increase in peroxisomal beta-oxidation was also n oted in the presence of etomoxir, another inhibitor of carnitine palmi toyltransferase 1. Exposure of hepatocytes to TDGA for 1 h led to an e xpected decrease in incorporation of radiolabel from [1-C-14]oleate in to CO2 and water-soluble products. In contrast, long-term exposure to TDGA increased incorporation of [1-C-14]oleate into oxidation products , most likely due to an adaptive induction of peroxisomal beta-oxidati on. Both acute and long-term exposure of hepatocytes to TDGA decreased incorporation of oleic acid into triglycerides, an effect that may ha ve contributed to the intracellular accumulation of fatty acids. These results provide support for a mechanism by which long-chain fatty aci ds or specific metabolites, including long-chain acyl-CoA esters and l ong-chain dicarboxylic acids, act as signals in the induction of P-450 4A1, peroxisomal beta-oxidation, and L-FABP under conditions in which long-chain fatty acids accumulate due to impaired entry into the mito chondrial beta-oxidation pathway.