A very long-chain acyl-CoA synthetase-deficient mouse and its relevance to X-linked adrenoleukodystrophy
A very long-chain acyl-CoA synthetase-deficient mouse and its relevance to X-linked adrenoleukodystrophy
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DOI：
10.1093/hmg/ddg126
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发表时间：
2003-05-15
影响因子：
3.5
通讯作者：
Smith, KD
中科院分区：
文献类型：
--
作者：
Heinzer, AK;Watkins, PA;Smith, KD
X-连锁肾上腺脑白质营养不良(X-ALD)是一种神经退行性和内分泌疾病，由编码ATP结合盒超家族中的过氧化物体膜蛋白的ABCD1突变引起。X-ALD的生化特征是组织和血浆中饱和超长链脂肪酸(VLCFA；22个或更多的碳链)水平增加，这与过氧化体超长链酰辅酶A合成酶(VLCs)活性降低和过氧化体VLCFA P氧化降低有关。ABCD1本身没有明显的VLCs活性，它通过转运脂肪酸底物、VLCs蛋白或某些必需的辅因子进入过氧体，间接影响VLCs的活性和VLCFA的β-氧化。在这里，我们报告了一种VICS基因敲除小鼠的特征，该小鼠表现出过氧体VLCs活性降低和VLCFA P-氧化，但不积累VLCFA。XALD/VICS双基因敲除小鼠具有个体基因敲除小鼠中观察到的生化异常，但没有表现出更严重的X-ALD表型。这些数据使我们得出结论：(1)VLCFA水平独立于过氧化体脂肪酸P-氧化，(2)没有ABCD1/VLCs相互作用，(3)在XALD小鼠中，常见的严重形式的X-ALD不能通过降低过氧化体VLCs活性来模拟。
X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative and endocrine disorder resulting from mutations in ABCD1 which encodes a peroxisomal membrane protein in the ATP binding cassette superfamily. The biochemical signature of X-ALD is increased levels of saturated very long-chain fatty acids (VLCFA; carbon chains of 22 or more) in tissues and plasma that has been associated with decreased peroxisomal very long-chain acyl-CoA synthetase (VLCS) activity and decreased peroxisomal VLCFA P-oxidation. It has been hypothesized that ABCD1, which has no demonstrable VLCS activity itself, has an indirect effect on peroxisomal VLCS activity and VLCFA beta-oxidation by transporting fatty acid substrates, VLCS protein or some required co-factor into peroxisomes. Here we report the characterization of a Vics knockout mouse that exhibits decreased peroxisomal VLCS activity and VLCFA P-oxidation but does not accumulate VLCFA. The XALD/Vics double knockout mouse has the biochemical abnormalities observed in the individual knockout mice but does not display a more severe X-ALD phenotype. These data lead us to conclude that (1) VLCFA levels are independent of peroxisomal fatty acid P-oxidation, (2) there is no ABCD1/VLCS interaction and (3) the common severe forms of X-ALD cannot be modeled by decreasing peroxisomal VLCS activity in the XALD mouse.