Localization of nervonic acid beta-oxidation in human and rodent peroxisomes: impaired oxidation in Zellweger syndrome and X-linked adrenoleukodystrophy.
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.
Sandhir
R
R
Division of Developmental Neurogenetics, Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA.
Khan
M
M
Chahal
A
A
Singh
I
I
D000326:Adrenoleukodystrophy / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D003066:Coenzyme A Ligases / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D008040:Genetic Linkage; D006801:Humans; D008830:Microbodies / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014960:X Chromosome; D015211:Zellweger Syndrome / Q000378:metabolism*; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; C013147:nervonic acid; D003066:Coenzyme A Ligases; C044125:lignoceroyl-CoA ligase; C090799:FAA2 protein, S cerevisiae; D000098859:Long-Chain-Fatty-Acid-CoA Ligase; C010210:lignoceric acid