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dc.contributor.authorMarques, André RA
dc.contributor.authorMirzaian, Mina
dc.contributor.authorAkiyama, Hisako
dc.contributor.authorWisse, Patrick
dc.contributor.authorFerraz, Maria J
dc.contributor.authorGaspar, Paulo
dc.contributor.authorGhauharali-van der Vlugt, Karen
dc.contributor.authorMeijer, Rianne
dc.contributor.authorGiraldo, Pilar
dc.contributor.authorAlfonso, Pilar
dc.contributor.authorIrún, Pilar
dc.contributor.authorDahl, Maria
dc.contributor.authorKarlsson, Stefan
dc.contributor.authorPavlova, Elena V
dc.contributor.authorCox, Timothy M
dc.contributor.authorScheij, Saskia
dc.contributor.authorVerhoek, Marri
dc.contributor.authorOttenhoff, Roelof
dc.contributor.authorvan Roomen, Cindy PAA
dc.contributor.authorPannu, Navraj S
dc.contributor.authorvan Eijk, Marco
dc.contributor.authorDekker, Nick
dc.contributor.authorBoot, Rolf G
dc.contributor.authorOverkleeft, Herman S
dc.contributor.authorBlommaart, Edward
dc.contributor.authorHirabayashi, Yoshio
dc.contributor.authorAerts, Johannes M
dc.date.accessioned2018-10-31T06:51:13Z
dc.date.available2018-10-31T06:51:13Z
dc.date.issued2016-03
dc.identifier.issn1539-7262
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284435
dc.description.abstractThe membrane lipid glucosylceramide (GlcCer) is continuously formed and degraded. Cells express two GlcCer-degrading β-glucosidases, glucocerebrosidase (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 (13)C6-labeled 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 disease, 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.
dc.description.sponsorshipThis study was made possible by the ERC AdG CHEMBIOSPHIN. The authors declare no financial conflicts of interest relevant to this study.
dc.languageeng
dc.publisherLipid Research, Inc.
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectGaucher disease
dc.subjectNiemann-Pick type C disease
dc.subjectglucocerebrosidase
dc.subjectglucosyl-β-D-cholesterol
dc.subjectglucosylceramide
dc.subjectAnimals
dc.subjectCOS Cells
dc.subjectCercopithecus aethiops
dc.subjectCholesterol
dc.subjectFemale
dc.subjectGaucher Disease
dc.subjectGlycosylation
dc.subjectHumans
dc.subjectMale
dc.subjectMice
dc.subjectNiemann-Pick Diseases
dc.subjectRAW 264.7 Cells
dc.subjectbeta-Glucosidase
dc.titleGlucosylated cholesterol in mammalian cells and tissues: formation and degradation by multiple cellular β-glucosidases.
dc.typeArticle
prism.endingPage463
prism.issueIdentifier3
prism.publicationDate2016
prism.publicationNameJournal of Lipid Research
prism.startingPage451
prism.volume57
dc.identifier.doi10.17863/CAM.31807
dcterms.dateAccepted2015-12-29
rioxxterms.versionofrecord10.1194/jlr.M064923
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2016-03
dc.contributor.orcidPavlova, Elena [0000-0003-0187-5098]
dc.contributor.orcidCox, Timothy [0000-0002-4951-9941]
dc.identifier.eissn1539-7262
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MR/K015338/1)
pubs.funder-project-idMedical Research Council (MR/K025570/1)
cam.issuedOnline2016-01-02


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International