Elongation of very long-chain fatty acids is enhanced in X-linked adrenoleukodystrophy

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• 作者：Kemp ; Stephan ; Valianpour ; Fredoen ; Denis ; Simone ; Ofman ; Rob ; Sanders ; Robert-Jan ; Mooyer ; Petra ; et. al.
• 关键词：X-linked adrenoleukodystrophy ; Very long-chain fatty acids ; VLCFA ; Peroxisome ; Elongation ; Lorenzo??????s oil ; Stable-isotope ; ????-Oxidation
• 刊名：Molecular Genetics and Metabolism
• 出版年：2005
• 出版时间：February, 2005
• 年：2005
• 卷：84
• 期：2
• 页码：144-151
• 全文大小：316 K

文摘

X-linked adrenoleukodystrophy (X-ALD) is a progressive neurodegenerative disorder characterized by the accumulation of saturated and mono-unsaturated very long-chain fatty acids (VLCFA) and reduced peroxisomal VLCFA ??-oxidation activity. In this study, we investigated the role of VLCFA biosynthesis in X-ALD fibroblasts. Our data demonstrate that elongation of both saturated and mono-unsaturated VLCFAs is enhanced in fibroblasts from patients with peroxisomal ??-oxidation defects including X-ALD, and peroxisome biogenesis disorders. These data indicate that enhanced VLCFA elongation is a general phenomenon associated with an impairment in peroxisomal ??-oxidation, and not specific for X-ALD alone. Analysis of plasma samples from patients with X-ALD and different peroxisomal ??-oxidation deficiencies revealed increased concentrations of VLCFAs up to 32 carbons. We infer that enhanced elongation does not result from impaired peroxisomal ??-oxidation alone, but is due to the additional effect of unchecked chain elongation. We demonstrate that elongated VLCFAs are incorporated into complex lipids. The role of chain elongation was also studied retrospectively in samples from patients with X-ALD previously treated with ???Lorenzo???s oil.??? We found that the decrease in plasma C26:0 previously found is offset by the increase of mono-unsaturated VLCFAs, not measured previously during the trial. We conclude that evaluation of treatment protocols for disorders of peroxisomal ??-oxidation making use of plasma samples should include the measurement of saturated and unsaturated VLCFAs of chain lengths above 26 carbon atoms. We also conclude that chain elongation offers an interesting target to be studied as a possible mode of treatment for X-ALD and other peroxisomal ??-oxidation disorders.