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
Rm. Kaikaus et al., 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 Journal of biological chemistry, 268(36), 1993, pp. 26866-26871
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.