Glucosylceramide accumulation is not confined to the lysosome in fibroblasts from patients with Gaucher disease
- 作者：Maria Fuller ; Tina Rozaklis ; Melanie Lovejoy ; Krystyna Zarrinkalam ; John J. Hopwood ; Peter J. Meikle
- 关键词：Sphingolipids ; Phospholipids ; Glucosylceramide ; Gaucher disease ; Mass spectrometry ; Lysosome ; Fibroblast
- 刊名：Molecular Genetics and Metabolism
- 出版年：2008
- 期刊代码：175_10967192
- 类别：bio
- 出版时间：April 2008
- 卷：93
- 期：4
- 页码：437-443
- 文件大小：283 K
摘要
Gaucher disease (GD) is an inborn error of glycosphingolipid metabolism resulting from a deficiency of the lysosomal enzyme β-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.