Glucosylceramide accumulation is not confined to the lysosome in fibroblasts from patients with Gaucher disease
Glucosylceramide accumulation is not confined to the lysosome in fibroblasts from patients with Gaucher disease
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DOI：
10.1016/j.ymgme.2007.11.011
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发表时间：
2008-04-01
影响因子：
3.8
通讯作者：
Meikle, Peter J.
中科院分区：
文献类型：
--
作者：
Fuller, Maria;Rozaklis, Tina;Meikle, Peter J.
高谢病(GD)是由于溶酶体酶P-葡萄糖苷酶缺乏导致葡萄糖神经酰胺(GC)在病细胞溶酶体内积聚而引起的一种先天性的神经鞘糖脂代谢障碍。为了确定GC蓄积对GD患者成纤维细胞内脂质含量的影响，我们用电喷雾电离-串联质谱仪测定了神经酰胺、二和三己糖神经酰胺、神经鞘蛋白、磷脂酰胆碱、磷脂酰肌醇和磷脂酰甘油的种类。每种脂类的不同亚种之间相互关联，并将其相加得到总脂浓度。除了GC，我们还注意到其他血脂的继发性升高，特别是在2型GD患者。亚细胞分级显示，GC不局限于溶酶体，而是在整个细胞内增加。溶酶体外堆积的后遗症可能通过与溶酶体外的生化和代谢途径相互作用而在GD的发病机制中发挥作用。在融合后4周，融合的2型GD成纤维细胞中神经酰胺的升高从最初聚集在溶酶体中的部位重新分布到内体区域。脂类在内酶体和溶酶体中的积累表明，脂类的运输受到了损害，溶酶体降解脂质的能力也降低了。(C)2007 Elsevier Inc.保留所有权利。
Gaucher disease (GD) is an inborn error of glycosphingolipid metabolism resulting from a deficiency of the lysosomal enzyme P-glucosidase leading to the accumulation of glucosylceramide (GC) in lysosomes of affected cells. In order to determine the effect of GC accumulation on intracellular lipid content in fibroblasts from patients with GD, we measured individual species of ceramide, di- and trihexosylceramide, sphingomyelin, phosphatidylcholine, phosphatidylinositol and phosphatidylglycerol using electrospray ionisation-tandem mass spectrometry. The different subspecies of each lipid class correlated with each other and were summed to give total lipid concentrations. In addition to GC, we also noted secondary elevations in other lipids, especially in type 2 GD. Sub-cellular fractionation showed that GC was not confined to the lysosome but increased throughout the cell. The sequelae of extra-lysosomal accumulation may have implications in the pathogenic mechanisms of GD by interaction with biochemical and metabolic pathways located outside the lysosome. The elevation of ceramide in confluent type 2 GD fibroblasts redistributed from its primary site of accumulation in the lysosome to the endosomal region at four-weeks post-confluence. The accumulation of lipids, in the endosome and lysosome suggests both impaired trafficking of lipids and reduced capacity of the lysosome to degrade lipids. (C) 2007 Elsevier Inc. All rights reserved.