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|Title:||Selective reduction of bis(monoacylglycero)phosphate ameliorates the storage burden in a THP-1 macrophage model of Gaucher disease|
|Citation:||Journal of Lipid Research, 2013; 54(6):1691-1697|
|Publisher:||Amer Soc Biochemistry Molecular Biology Inc|
|Leanne K. Hein, Stephen Duplock, and Maria Fuller|
|Abstract:||Bis(monoacylglycero)phosphate (BMP) assists lysosomal function by facilitating interaction of hydrolases and activator proteins with sphingolipid substrates. Impaired lysosomal degradation of the sphingolipid glucosylceramide (GC) occurs in Gaucher disease due to an inherited deficiency of acid β-glucosidase, with secondary BMP alterations. We investigated the nature of BMP accumulation and whether its correction reduced the storage burden in a THP-1 macrophage model of Gaucher disease. Using sucrose gradients and detergent solubility, 98% of BMP resided in the detergent-soluble membranes (DSM) rather than in the detergent-resistant membranes (DRM) where 73% of GC predominated. There was a 2-fold widespread elevation in BMP, including the saturated, mono- and polyunsaturated species. Linoleic acid in the culture media selectively reduced BMP from 4.2 nmol/mg to 0.49 nmol/mg (except 18:1/18:2) and prevented up to one third of GC, dihexosylceramide (DHC), and trihexosylceramide (THC) from accumulating. The 2-fold reduction in these sphingolipids occurred only in the DRM and did not reduce 18:1/16:0. However, once GC had accumulated, linoleic acid could not reverse it, DHC, or THC, despite effectively reducing BMP. These results imply a causative link for BMP in the pathobiology of Gaucher disease and demonstrate that linoleic acid can shield the cell from excessive substrate accumulation.|
|Keywords:||detergent-resistant membranes; fatty acids; glucosylceramide; lysosomal disease; lysosomal dysfunction; lysosomal storage disorder; mass spectrometry; membrane microdomains|
|Rights:||Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc.|
|Appears in Collections:||Paediatrics publications|
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