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Abstract
Sphingosine-1-phosphate (S1P) mediates several cytoprotective functions of HDL. apoM acts as a S1P binding protein in HDL. Erythrocytes are the major source of S1P in plasma. After glomerular filtration, apoM is endocytosed in the proximal renal tubules. Human or murine HDL elicited time- and dose-dependent S1P efflux from erythrocytes. Compared with HDL of wild-type (wt) mice, S1P efflux was enhanced in the presence of HDL from apoM transgenic mice, but not diminished in the presence of HDL from apoM knockout (Apom(-/-)) mice. Artificially reconstituted and apoM-free HDL also effectively induced S1P efflux from erythrocytes. S1P and apoM were not measurable in the urine of wt mice. Apom(-/-) mice excreted significant amounts of S1P. apoM was detected in the urine of mice with defective tubular endocytosis because of knockout of the LDL receptor-related protein, chloride-proton exchanger ClC-5 (Clcn5(-/-)), or the cysteine transporter cystinosin. Urinary levels of S1P were significantly elevated in Clcn5(-/-) mice. In contrast to Apom(-/-) mice, these mice showed normal plasma concentrations for apoM and S1P. In conclusion, HDL facilitates S1P efflux from erythrocytes by both apoM-dependent and apoM-independent mechanisms. Moreover, apoM facilitates tubular reabsorption of S1P from the urine, however, with no impact on S1P plasma concentrations.
Highlights
Sphingosine-1-phosphate (S1P) mediates several cytoprotective functions of HDL. apoM acts as a S1P binding protein in HDL
We monitored the time-dependent S1P efflux from erythrocytes in the presence of 300 g/ml HDLs which were isolated from the plasma of wt, apoM knockout mice (ApomϪ/Ϫ), or mice transgenic for apoM (Apomtg) mice in comparison with 300 g/ml albumin
The maximal net S1P efflux measured was significantly increased in the presence of HDL from Apomtg mice, but not decreased in the presence of HDL from ApomϪ/Ϫ mice (Fig. 1D)
Summary
Sphingosine-1-phosphate (S1P) mediates several cytoprotective functions of HDL. apoM acts as a S1P binding protein in HDL. ApoM acts as a S1P binding protein in HDL. Reconstituted and apoM-free HDL effectively induced S1P efflux from erythrocytes. ApoM was detected in the urine of mice with defective tubular endocytosis because of knockout of the LDL receptor-related protein, chloride-proton exchanger ClC-5 (Clcn5؊/؊), or the cysteine transporter cystinosin. HDL facilitates S1P efflux from erythrocytes by both apoMdependent and apoM-independent mechanisms. ApoM facilitates tubular reabsorption of S1P from the urine, with no impact on S1P plasma concentrations.—Sutter, I., R. The majority of S1P is transported by HDLs in which it exerts many cyto-protective and anti-inflammatory effects, for example, on endothelial cells [8,9,10]. Purified and recombinant apoM binds S1P with an IC50 of 0.9 mol/l, which is in the range of physiological S1P plasma concentrations [11].
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