Sutter Iryna, Park Rebekka, Othman Alaa, Rohrer Lucia, Hornemann Thorsten, Stoffel Markus, Devuyst Olivier, von Eckardstein Arnold
Institute of Clinical Chemistry, University and University Hospital of Zurich, Zurich, Switzerland; Competence Center for Integrated Human Physiology and Institute of Physiology.
ETH Zurich, Zurich, Switzerland; and Competence Center for Systems Physiology and Metabolic Diseases ETH Zurich and University of Zurich, Zurich, Switzerland.
J Lipid Res. 2014 Aug;55(8):1730-7. doi: 10.1194/jlr.M050021. Epub 2014 Jun 20.
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.
鞘氨醇-1-磷酸（S1P）介导高密度脂蛋白（HDL）的多种细胞保护功能。载脂蛋白M（apoM）作为HDL中的一种S1P结合蛋白。红细胞是血浆中S1P的主要来源。经肾小球滤过后，apoM在近端肾小管中被内吞。人或小鼠的HDL可引起红细胞中S1P呈时间和剂量依赖性流出。与野生型（wt）小鼠的HDL相比，apoM转基因小鼠的HDL存在时S1P流出增强，但在apoM基因敲除（Apom(-/-)）小鼠的HDL存在时并未减弱。人工重组且不含apoM的HDL也能有效诱导红细胞中S1P流出。wt小鼠尿液中无法检测到S1P和apoM。Apom(-/-)小鼠排泄大量S1P。在因低密度脂蛋白受体相关蛋白、氯-质子交换体ClC-5（Clcn5(-/-)）或半胱氨酸转运体胱氨酸转运蛋白敲除而导致肾小管内吞缺陷的小鼠尿液中检测到apoM。Clcn5(-/-)小鼠尿液中S1P水平显著升高。与Apom(-/-)小鼠不同，这些小鼠的apoM和S1P血浆浓度正常。总之，HDL通过依赖apoM和不依赖apoM的机制促进红细胞中S1P流出。此外，apoM促进肾小管从尿液中重吸收S1P，然而，对S1P血浆浓度没有影响。
