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

Marques, André R A ; Mirzaian, Mina ; Akiyama, Hisako ; Wisse, Patrick ; Ferraz, Maria J ; Gaspar, Paulo ; Ghauharali-van der Vlugt, Karen ; Meijer, Rianne ; Giraldo, Pilar and Alfonso, Pilar , et al. (2016) In Journal of Lipid Research 57. p.451-463
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Lipid Research
volume
57
pages
451 - 463
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • pmid:26724485
  • wos:000371095500014
  • scopus:84964329661
  • pmid:26724485
ISSN
1539-7262
DOI
10.1194/jlr.M064923
language
English
LU publication?
yes
id
8c8143f6-5974-496e-b772-c9d8c3bbae70 (old id 8593325)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26724485?dopt=Abstract
date added to LUP
2016-04-04 07:07:43
date last changed
2022-04-23 07:46:29
@article{8c8143f6-5974-496e-b772-c9d8c3bbae70,
  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.}},
  author       = {{Marques, André R A and Mirzaian, Mina and Akiyama, Hisako and Wisse, Patrick and Ferraz, Maria J and Gaspar, Paulo and Ghauharali-van der Vlugt, Karen and Meijer, Rianne and Giraldo, Pilar and Alfonso, Pilar and Irún, Pilar and Dahl, Maria and Karlsson, Stefan and Pavlova, Elena V and Cox, Timothy M and Scheij, Saskia and Verhoek, Marri and Ottenhoff, Roelof and van Roomen, Cindy P A A and Pannu, Navraj S and van Eijk, Marco and Dekker, Nick and Boot, Rolf G and Overkleeft, Herman S and Blommaart, Edward and Hirabayashi, Yoshio and Aerts, Johannes M}},
  issn         = {{1539-7262}},
  language     = {{eng}},
  month        = {{01}},
  pages        = {{451--463}},
  publisher    = {{American Society for Biochemistry and Molecular Biology}},
  series       = {{Journal of Lipid Research}},
  title        = {{Glucosylated cholesterol in mammalian cells and tissues: formation and degradation by multiple cellular β-glucosidases.}},
  url          = {{http://dx.doi.org/10.1194/jlr.M064923}},
  doi          = {{10.1194/jlr.M064923}},
  volume       = {{57}},
  year         = {{2016}},
}