Studies with purified subcellular organelles from rat liver indicate that
nervonic acid (C24:1) is beta-oxidized preferentially in peroxisomes. Lack of effect by
etomoxir, inhibitor of mitochondrial beta-oxidation, on beta-oxidation of
lignoceric acid (C24:0), a peroxisomal function, and that of
nervonic acid (24:1) compared to the inhibition of
palmitic acid (16:0) oxidation, a mitochondrial function, supports the conclusion that
nervonic acid is oxidized in peroxisomes. Moreover, the oxidation of nervonic and lignoceric
acids was deficient in fibroblasts from patients with defects in peroxisomal beta-oxidation [
Zellweger syndrome (ZS) and
X-linked adrenoleukodystrophy (
X-ALD)]. Similar to
lignoceric acid, the activation and beta-oxidation of
nervonic acid was deficient in peroxisomes isolated from
X-ALD fibroblasts. Transfection of
X-ALD fibroblasts with human
cDNA encoding for ALDP (
X-ALD gene product) restored the oxidation of both nervonic and lignoceric
acids, demonstrating that the same molecular defect may be responsible for the abnormality in the oxidation of nervonic as well as
lignoceric acid. Moreover, immunoprecipitation of activities for
acyl-CoA ligase for both
lignoceric acid and
nervonic acid indicate that saturated and monoenoic very long chain (VLC)
fatty acids may be activated by the same
enzyme. These results clearly demonstrate that similar to saturated VLC
fatty acids (e.g.,
lignoceric acid), VLC
monounsaturated fatty acids (e.g.,
nervonic acid) are oxidized preferentially in peroxisomes and that this activity is impaired in
X-ALD. In view of the fact that the oxidation of unsaturated VLC
fatty acids is defective in
X-ALD patients, the efficacy of dietary monoene
therapy, "
Lorenzo's oil," in
X-ALD needs to be evaluated.