X-linked adrenoleukodystrophy: role of very long-chain acyl-CoA synthetases

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• 作者：Jia ; Zhenzhen ; Pei ; Zhengtong ; Li ; Yuanyuan ; Wei ; Liumei ; Smith ; Kirby D. ; Watkins ; Paul A.
• 关键词：X-linked adrenoleukodystrophy ; Very long-chain acyl-CoA synthetase ; Fatty acid metabolism ; Fatty acid activation ; Bubblegum ; Peroxisome ; Fatty acid transport protein ; Mouse models ; Neurodegenerative diseases
• 刊名：Molecular Genetics and Metabolism
• 出版年：2004
• 出版时间：September - October, 2004
• 年：2004
• 卷：83
• 期：1-2
• 页码：117-127
• 全文大小：1.20 M

文摘

The principal biochemical abnormality in the neurodegenerative disorder X-linked adrenoleukodystrophy (X-ALD) is elevated plasma and tissue levels of very long-chain fatty acids (VLCFA). Enzymes with very long-chain acyl-CoA synthetase (VLACS) activity are required for VLCFA metabolism, including degradation by peroxisomal ??-oxidation or incorporation into complex lipids, and may also participate in VLCFA synthesis. Two enzymes with VLACS activity, ACSVL1 and BG1, were investigated for their potential role in X-ALD biochemical pathology. Skin fibroblast mRNA levels for ACSVL1, an enzyme previously shown to be in peroxisomes and to participate in VLCFA ??-oxidation, were not significantly different between normal controls, patients with childhood cerebral X-ALD, and patients with adrenomyeloneuropathy. Similar results were obtained with mRNA for BG1, a non-peroxisomal enzyme that is highly expressed in nervous system, adrenal gland, and testis, the principal tissues pathologically affected in X-ALD. No significant differences in the immunohistochemical staining patterns of tissues expressing either ACSVL1 or BG1 were observed when wild-type and X-ALD mice were compared. Western blot analysis of BG1 protein levels showed no differences between fibroblasts from controls, cerebral X-ALD, or adrenomyeloneuropathy patients. BG1 protein levels were similar in wild-type and X-ALD mouse brain, spinal cord, testis, and adrenal gland. We hypothesized that one function of BG1 was to direct VLCFA into the cholesterol ester synthesis pathway. However, BG1 depletion in Neuro2a cells using RNA interference did not decrease incorporation of labeled VLCFA into cholesterol esters. We conclude that the role, if any, of ACSVL1 and BG1 in X-ALD biochemical pathology is indirect.