Glucosylated cholesterol in mammalian cells and tissues: formation and degradation by multiple cellular β-glucosidases

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Glucosylated cholesterol in mammalian cells and tissues: formation and degradation by multiple cellular β-glucosidases

Type: Article / Letter to editor
Title: Glucosylated cholesterol in mammalian cells and tissues: formation and degradation by multiple cellular β-glucosidases
Author: Marques, A.R.Mirzaian, M.Akiyama, H.Wisse, P.Ferraz, M.J.Gaspar, P.Ghauharali-van, der Vlugt K.Meijer, R.Giraldo, P.Alfonso, P.Irún, P.Dahl, M.Karlsson, S.Pavlova, E.V.Cox, T.M.Scheij, S.Verhoek, M.Ottenhoff, R.Roomen, C.P. vanPannu, N.S.van, Eijk M.Dekker, N.Boot, R.G.Overkleeft, H.S.Blommaart, E.Hirabayashi, Y.Aerts, J.M.
Journal Title: Journal of Lipid Research
Volume: 57
Start Page: 451
End Page: 463
Pages: 13
Issue Date: 2016
Abstract: The membrane lipid glucosylceramide (GlcCer) is continuously formed and degraded. Cells express two GlcCer-degrading β-glucosidases, GBA and GBA2, located in and outside the lysosome, respectively. Here we demonstrate that through transglucosylation both GBA and GBA2 are able to catalyze in vitro the transfer of glucosyl-moieties from GlcCer to cholesterol, and vice versa. Furthermore, the natural occurrence of 1-O-cholesteryl-β-D-glucopyranoside (GlcChol) in mouse tissues and human plasma is demonstrated using LC-MS/MS and 13C6-labelled GlcChol as internal standard. In cells the inhibition of GBA increases GlcChol, whereas inhibition of GBA2 decreases glucosylated sterol. Similarly, in GBA2-deficient mice GlcChol is reduced. Depletion of GlcCer by inhibition of GlcCer synthase decreases GlcChol in cells and likewise in plasma of inhibitor-treated Gaucher disease patients. In tissues of mice with Niemann-Pick type C, a condition characterized by intralysosomal accumulation of cholesterol, marked elevations in GlcChol occur as well. When lysosomal accumulation of cholesterol is induced in cultured cells, GlcChol is formed via lysosomal GBA. This illustrates that reversible transglucosylation reactions are highly dependent on local availability of suitable acceptors. In conclusion, mammalian tissues contain GlcChol formed by transglucosylation through β-glucosidases using GlcCer as donor. Our findings reveal a novel metabolic function for GlcCer.
Handle: http://hdl.handle.net/1887/43132
 

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