Abstract
Studies with purified subcellular organelles from rat liver indicate that nervonic acid (C24:1) is β-oxidized preferentially in peroxisomes. Lack of effect by etomoxir, inhibitor of mitochondrial β-oxidation, on β-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 β-oxidation [Zellweger syndrome (ZS) and X-linked adrenoleukodystrophy (X-ALD)]. Similar to lignoceric acid, the activation and β-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. —Sandhir, R., M. Khan, A. Chahal, and I. Singh. Localization of nervonic acid β-oxidation in human and rodent peroxisomes: impaired oxidation in Zellweger syndrome and X-linked adrenoleukodystrophy. J. Lipid Res. 1998. 39: 2161–2171.
Highlights
Studies with purified subcellular organelles from rat liver indicate that nervonic acid (C24:1) is -oxidized preferentially in peroxisomes
The studies described in this manuscript clearly demonstrate that both saturated and unsaturated very long chain (VLC) fatty acids are -oxidized in peroxisomes in rodents as well as in humans
In agreement with our previous observations, the activity for oxidation of lignoceric acid was observed in peroxisomes and that for palmitic acid was observed in both peroxisomes and mitochondria [29]
Summary
Studies with purified subcellular organelles from rat liver indicate that nervonic acid (C24:1) is -oxidized preferentially in peroxisomes. 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. Studies from our laboratory [6, 7] and others [8] have previously demonstrated that saturated VLC fatty acids are preferentially and possibly exclusively oxidized in peroxisomes, and accumulate in pathognomonic amounts in peroxisomal disorders with defects in their -oxidation such as Zellweger syndrome (ZS) and Xlinked adrenoleukodystrophy (X-ALD). Saturated VLC fatty acids are oxidized in peroxisomes and excessive accumulation of saturated fatty acids in X-ALD is due to their impaired -oxidation because of the abnormality in lignoceroyl-CoA ligase activity [14]. This implies that the therapy of X-ALD patients with “Lorenzo’s oil” should be re-evaluated in case monoenoic VLC fatty acids are oxidized by the same enzyme system as the saturated VLC fatty acids
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