title: Apolipoprotein M modulates erythrocyte efflux and tubular reabsorption of sphingosine-1-phosphate.
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.
authors.affiliation: Institute of Clinical Chemistry, University and University Hospital of Zurich, Zurich, Switzerland; Competence Center for Integrated Human Physiology and Institute of Physiology.
authors.forename: Iryna
authors.initials: I
authors.lastname: Sutter
authors.affiliation: ETH Zurich, Zurich, Switzerland; and Competence Center for Systems Physiology and Metabolic Diseases ETH Zurich and University of Zurich, Zurich, Switzerland.
authors.forename: Rebekka
authors.initials: R
authors.lastname: Park
authors.affiliation: Institute of Clinical Chemistry, University and University Hospital of Zurich, Zurich, Switzerland; Competence Center for Integrated Human Physiology ETH Zurich and University of Zurich, Zurich, Switzerland.
authors.forename: Alaa
authors.initials: A
authors.lastname: Othman
authors.affiliation: Institute of Clinical Chemistry, University and University Hospital of Zurich, Zurich, Switzerland; Competence Center for Integrated Human Physiology and Institute of Physiology.
authors.forename: Lucia
authors.initials: L
authors.lastname: Rohrer
authors.affiliation: Institute of Clinical Chemistry, University and University Hospital of Zurich, Zurich, Switzerland; Competence Center for Integrated Human Physiology and Institute of Physiology.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hornemann
authors.affiliation: ETH Zurich, Zurich, Switzerland; and Competence Center for Systems Physiology and Metabolic Diseases ETH Zurich and University of Zurich, Zurich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Stoffel
authors.affiliation: and Institute of Physiology University of Zurich, Zurich, Switzerland; Institute of Molecular Health Sciences.
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.affiliation: Institute of Clinical Chemistry, University and University Hospital of Zurich, Zurich, Switzerland; Competence Center for Integrated Human Physiology and Institute of Physiology ETH Zurich and University of Zurich, Zurich, Switzerland.
authors.forename: Arnold
authors.initials: A
authors.lastname: von Eckardstein
mesh_terms: D000818:Animals; D000075243:Apolipoproteins M / Q000235:genetics / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism
chemical_list: C501623:ApoM protein, mouse; D000075243:Apolipoproteins M; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D013110:Sphingosine
keywords: chloride-proton exchanger ClC5; cystinosin; high density lipoprotein; kidney; megalin