Plasma glucosylceramide deficiency as potential risk factor for venous thrombosis and modulator of anticoagulant protein C pathway

Abstract

To assess the relationship between venous thrombosis and plasma glucosylceramide (GlcCer) or phosphatidylethanolamine (PE), plasma levels of GlcCer and PE were determined for 70 venous thrombosis patients referred for evaluation and 70 healthy blood donors. The mean GlcCer level, but not the PE level, was lower in patients versus controls (4.9 vs 6.5 g/mL [P ‫؍‬ .0007] and 66 vs 71 g/mL [P ‫؍‬ .48], respectively). As a measure of relative risk, the odds ratio for deep vein thrombosis in subjects with GlcCer levels below the 10th percentile of controls was 5.7 (95% CI, 2.3-14). To assess the influence of glycolipids on anticoagulant response to activated protein C (APC):protein S in modified prothrombin time assays, the effects of depleting endogenous plasma GlcCer by glucocerebrosidase treatment or of adding exogenous purified GlcCer or other neutral glycolipids to plasma were tested. Glucocerebrosidase treatment reduced plasma sensitivity to APC: protein S in parallel with GlcCer reduction. Exogenously added GlcCer and the homologous Glc-containing globotriaosylceramide (Gb3Cer), but not galactosylceramide, dose-dependently prolonged clotting times of normal plasma in the presence, but not absence, of APC:protein S, which suggests that GlcCer or Gb3Cer can enhance protein C pathway anticoagulant activity. In studies using purified proteins, inactivation of factor Va by APC:protein S was enhanced by GlcCer alone and by GlcCer in multicomponent vesicles containing phosphatidylserine and phosphatidylcholine. These results suggest that the neutral glycolipids GlcCer and Gb3Cer may directly contribute to the anticoagulant activity of the protein C pathway and that deficiency of plasma GlcCer may be a risk factor for venous thrombosis. (Blood. 2001;97: 1907-1914

The cytoprotective protein C pathway

“…Whether APC-induced S1P up-regulation and concomitant ceramide and sphingosine down-regulation contribute to APC antiapoptotic activity is currently unclear. Glucosylceramide, a major metabolic product of ceramide, enhances APC anticoagulant activity, 67,68 suggesting that interactions between the sphingolipid regulatory pathway and the protein C pathways might be both more complicated and more significant than previously appreciated.…”

Regulating survival and development in the retina: key roles for simple sphingolipids

“…GlcCers participate in cellular processes such as cell proliferation, oncogenic transformation, differentiation, and tumor metastasis ( 119,120 ). Modulation of GCS can signifi cantly affect the apoptotic mechanism ( 119 ).…”

Neutral glycosphingolipids in human blood: a precise mass spectrometry analysis with special reference to lipoprotein-associated Shiga toxin receptors

“…This prompted us to perform a compositional analysis of neutral GSLs in human blood with special reference to monohexosylceramides and Stx receptors and their association with lipoproteins. Notably, glucosylceramide (GlcCer) has been reported to modulate the Stx-mediated cytotoxic effect ( 34 ) and may directly contribute to venous thrombosis ( 35 ), and galactosylceramide (GalCer) has been identifi ed as a (co)receptor of type 1 human immunodeficiency virus ( 36,37 ).…”

“…Furthermore, Zama et al ( 70 ) recently published a novel HPLC-based technology to simultaneously analyze and quantify GalCer and GlcCer using o-phthalaldehyde derivatives prepared with sphingolipid ceramide N -deacylase. Due to the biological importance, for example, of GalCer as (co)receptor of HIV-1 gp120 and gp41 ( 36,37 ) or GlcCer exhibiting thrombosis modulatory potential ( 35 ) and auxiliary function in Stx-mediated cytotoxicity ( 34 ), those techniques might be useful for the determination of GlcCer and GalCer levels in various biological samples such as target tissues or body fl uids.…”