Localization of nervonic acid beta-oxidation in human and rodent peroxisomes: impaired oxidation in Zellweger syndrome and X-linked adrenoleukodystrophy.
Localization of nervonic acid beta-oxidation in human and rodent peroxisomes: impaired oxidation in Zellweger syndrome and X-linked adrenoleukodystrophy.
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发表时间：
1998-11
影响因子：
6.5
通讯作者：
R. Sandhir;M. Khan;A. Chahal;I. Singh
中科院分区：
文献类型：
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作者：
R. Sandhir;M. Khan;A. Chahal;I. Singh
从大鼠肝脏纯化的亚细胞器的研究表明，神经酸（C24：1）是β-氧化优先在过氧化物酶体。与抑制棕榈酸（16：0）氧化（一种线粒体功能）相比，依托莫西（线粒体β-氧化抑制剂）对二十四酸（C24：0）（一种过氧化物酶体功能）和神经酸（24：1）的β-氧化缺乏影响，这支持神经酸在过氧化物酶体中被氧化的结论。此外，过氧化物酶体β-氧化缺陷患者[Zellweger综合征（ZS）和X连锁肾上腺脑白质营养不良（X-ALD）]的成纤维细胞中神经酸和二十四烷酸的氧化不足。与二十四烷酸类似，神经酸的活化和β-氧化在从X-ALD成纤维细胞分离的过氧化物酶体中缺乏。用编码ALDP（X-ALD基因产物）的人cDNA转染X-ALD成纤维细胞恢复了神经酸和二十四烷酸的氧化，表明相同的分子缺陷可能是神经酸和二十四烷酸氧化异常的原因。此外，木蜡酸和神经酸的酰基辅酶A连接酶的活性的免疫沉淀表明，饱和和单烯极长链（VLC）脂肪酸可以被相同的酶激活。这些结果清楚地表明，类似于饱和VLC脂肪酸（例如，二十四烷酸），VLC单不饱和脂肪酸（例如，神经酸）优先在过氧化物酶体中氧化，并且这种活性在X-ALD中受损。鉴于不饱和VLC脂肪酸的氧化在X-ALD患者中是有缺陷的，需要评估饮食单烯疗法“洛伦佐油”在X-ALD中的功效。
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.