Glycosphingoid bases are elevated in inherited lysosomal storage disorders with deficient activity of glycosphingolipid catabolizing glycosidases. We investigated the molecular basis of the formation of glucosylsphingosine and globotriaosylsphingosine during deficiency of glucocerebrosidase (Gaucher disease) and α‐galactosidase A (Fabry disease). Independent genetic and pharmacological evidence is presented pointing to an active role of acid ceramidase in both processes through deacylation of lysosomal glycosphingolipids. The potential pathophysiological relevance of elevated glycosphingoid bases generated through this alternative metabolism in patients suffering from lysosomal glycosidase defects is discussed.

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The 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 13C6-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.

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BackgroundWe retrospectively compared biochemical responses in type 1 Gaucher disease patients to treatment with glycosphingolipid synthesis inhibitors miglustat and eliglustat and ERT.MethodsSeventeen GD1 patients were included (n = 6 eliglustat, (two switched from ERT), n = 9 miglustat (seven switchers), n = 4 ERT (median dose 60U/kg/m). Plasma protein markers reflecting disease burden (chitotriosidase, CCL18) and lipids reflecting substrate accumulation (glucosylsphingosine, glucosylceramide) were determined. Also, liver and spleen volumes, hemoglobin, platelets, and fat fraction were measured.ResultsIn patients naïve to treatment, chitotriosidase, CCL18 and glucosylsphingosine decreased comparably upon eliglustat and ERT treatment, while the response to miglustat was less. After 2 years, median decrease of chitotriosidase was 89 % (range 77–98), 88 % (78–92) and 37 % (29–46) for eliglustat, ERT and miglustat naïve patients respectively; decrease of CCL18 was 73 % (63–78), 54 % (43–86), and 10 % (3–18); decrease of glucosylsphingosine was 86 % (78–93), 78 % (65–91), 48 % (46–50). Plasma glucosylceramide in eliglustat treated patients (n = 4) reached values below the normal range (n = 20 healthy controls). Biochemical markers decreased or stabilized in switchers from ERT to eliglustat (n = 2), but less in miglustat switchers (n = 7). Clinical parameters responded comparably upon eliglustat and ERT treatment.ConclusionsOur explorative study provides evidence that biochemical markers respond comparably in patients receiving eliglustat treatment and ERT, while the corresponding response to miglustat treatment is less.