Elevated globotriaosylsphingosine is a hallmark of Fabry disease
Elevated globotriaosylsphingosine is a hallmark of Fabry disease
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DOI：
10.1073/pnas.0712309105
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发表时间：
2008-02-26
影响因子：
11.1
通讯作者：
Poorthuis, Ben J.
中科院分区：
文献类型：
--
作者：
Aerts, Johannes M.;Groener, Johanna E.;Poorthuis, Ben J.
法布里病是一种由α -半乳糖苷酶A缺乏引起的x连锁溶酶体贮积病，影响男性，并在杂合子中表现出疾病表达。进行性肾功能不全、心脏受累和神经病理的特征性表现通常归因于内皮细胞中球三神经酰胺的积累。然而，脂质储存与临床表现之间不存在直接相关性，并且尽管内皮细胞中的脂质被清除，但重组酶治疗患者并不能逆转一些关键体征。因此，我们研究了globotriaosylneuroide代谢物在发病机制中缺失一环的可能性。我们报道，脱酰化的globotriaosyl神经酰胺、globotriaosylsphingosine和一种少量的附加代谢物在典型法布里男性患者和法布里小鼠的血浆和组织中显著增加。治疗后血浆球三神经酰胺水平降低。我们发现globotriaosylsphingosin是α -半乳糖苷酶A活性的抑制剂。此外，平滑肌细胞，而不是成纤维细胞，暴露于患者血浆中观察到的浓度的globotriaosylsphingosin促进了增殖。因此，Fabry患者内膜中膜厚度的增加可能与这种代谢物的存在有关。我们的研究结果表明，循环globotriaosylsphingosin的测量将有助于监测法布里病，并有助于更好地了解这种疾病。
Fabry disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A that affects males and shows disease expression in heterozygotes. The characteristic progressive renal insufficiency, cardiac involvement, and neuropathology usually are ascribed to globotriaosylceramide accumulation in the endothelium. However, no direct correlation exists between lipid storage and clinical manifestations, and treatment of patients with recombinant enzymes does not reverse several key signs despite clearance of lipid from the endothelium. We therefore investigated the possibility that globotriaosylceramide metabolites are a missing link in the pathogenesis. We report that deacylated globotriaosylceramide, globotriaosylsphingosine, and a minor additional metabolite are dramatically increased in plasma of classically affected male Fabry patients and plasma and tissues of Fabry mice. Plasma globotriaosylceramide levels are reduced by therapy. We show that globotriaosylsphingosine is an inhibitor of alpha-galactosidase A activity. Furthermore, exposure of smooth muscle cells, but not fibroblasts, to globotriaosylsphingosine at concentrations observed in plasma of patients promotes proliferation. The increased intima-media thickness in Fabry patients therefore may be related to the presence of this metabolite. Our findings suggest that measurement of circulating globotriaosylsphingosine will be useful to monitor Fabry disease and may contribute to a better understanding of the disorder.