Determinants of Serum- and Plasma Sphingosine-1-Phosphate Concentrations in a Healthy Study Group

Abstract

Introduction To correctly interpret plasma- or serum-sphingosine-1-phosphate (S1P) concentrations measured in clinical studies it is critical to understand all major determinants in healthy controls.

Methods Serum- and plasma-S1P from 174 healthy blood donors was measured by liquid chromatography-tandem mass spectrometry and correlated to clinical laboratory data. Selected plasma samples, 10 with high and 10 with low S1P concentrations, were fractionated into very low-density lipoprotein (VLDL)-, low density lipoprotein (LDL)-, high density lipoprotein (HDL)-, and lipoprotein-free fractions. S1P was then measured in each fraction to determine its distribution.

Results The mean S1P concentration in serum (1.04 ± 0.24 nmol/mL) was found 39% higher compared with plasma (0.75 ± 0.16 nmol/mL) and overall was not different between men and women. Only when stratified for age and gender, older women were found to exhibit higher circulatory S1P levels than men. In plasma, S1P levels correlate to red blood cell (RBC) counts but not to platelet counts. Conversely, serum-S1P correlates to platelet counts but not to RBC counts. In addition, eosinophil counts are strongly associated with serum-S1P concentrations. Both serum- and plasma-S1P correlate to total cholesterol but not to HDL-C. The distribution of S1P between VLDL-, LDL-, HDL-, and lipoprotein-free fractions is independent of total plasma-S1P concentrations. S1P concentrations in HDL but not in LDL are highly variable.

Conclusion These data indicate S1P concentrations in plasma and serum to be differentially associated with cell counts and S1P carrier proteins. Besides platelets, eosinophil counts are identified as a novel determinant for serum-S1P concentrations further suggesting a role for S1P in eosinophil pathologies.

Keywords

sphingosine-1-phosphate - lipoproteins - blood

• References

• 1 Proia RL, Hla T. Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest 2015; 125 (04) 1379-1387
• 2 Pyne NJ, Pyne S. Sphingosine 1-phosphate receptor 1 signaling in mammalian cells. Molecules 2017; 22 (03) 22
• 3 Magaye RR, Savira F, Hua Y. , et al. The role of dihydrosphingolipids in disease. Cell Mol Life Sci 2019; 76 (06) 1107-1134
• 4 Murata N, Sato K, Kon J. , et al. Interaction of sphingosine 1-phosphate with plasma components, including lipoproteins, regulates the lipid receptor-mediated actions. Biochem J 2000; 352 (Pt 3): 809-815
• 5 Wang L, Dudek SM. Regulation of vascular permeability by sphingosine 1-phosphate. Microvasc Res 2009; 77 (01) 39-45
• 6 Sanchez T. Sphingosine-1-phosphate signaling in endothelial disorders. Curr Atheroscler Rep 2016; 18 (06) 31
• 7 Winkler MS, Nierhaus A, Poppe A, Greiwe G, Gräler MH, Daum G. Sphingosine-1-phosphate: a potential biomarker and therapeutic target for endothelial dysfunction and sepsis?. Shock 2017; 47 (06) 666-672
• 8 Cyster JG, Schwab SR. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu Rev Immunol 2012; 30: 69-94
• 9 Yanagida K, Hla T. Vascular and immunobiology of the circulatory sphingosine 1phosphate gradient. Annu Rev Physiol 2017; 79: 67-91
• 10 Gomes L, Fernando S, Fernando RH. , et al. Sphingosine 1-phosphate in acute dengue infection. PLoS One 2014; 9 (11) e113394
• 11 Michels M, Japtok L, Alisjahbana B. , et al. Decreased plasma levels of the endothelial protective sphingosine-1-phosphate are associated with dengue-induced plasma leakage. J Infect 2015; 71 (04) 480-487
• 12 Wang Z, Sims CR, Patil NK, Gokden N, Mayeux PR. Pharmacologic targeting of sphingosine-1-phosphate receptor 1 improves the renal microcirculation during sepsis in the mouse. J Pharmacol Exp Ther 2015; 352 (01) 61-66
• 13 Winkler MS, Nierhaus A, Holzmann M. , et al. Decreased serum concentrations of sphingosine-1-phosphate in sepsis. Crit Care 2015; 19: 372
• 14 Deutschman DH, Carstens JS, Klepper RL. , et al. Predicting obstructive coronary artery disease with serum sphingosine-1-phosphate. Am Heart J 2003; 146 (01) 62-68
• 15 Sattler KJ, Elbasan S, Keul P. , et al. Sphingosine 1-phosphate levels in plasma and HDL are altered in coronary artery disease. Basic Res Cardiol 2010; 105 (06) 821-832
• 16 Soltau I, Mudersbach E, Geissen M. , et al. Serum-sphingosine-1-phosphate concentrations are inversely associated with atherosclerotic diseases in humans. PLoS One 2016; 11 (12) e0168302
• 17 Ono Y, Kurano M, Ohkawa R. , et al. Sphingosine 1-phosphate release from platelets during clot formation: close correlation between platelet count and serum sphingosine 1-phosphate concentration. Lipids Health Dis 2013; 12: 20
• 18 Yatomi Y, Ruan F, Hakomori S, Igarashi Y. Sphingosine-1-phosphate: a platelet-activating sphingolipid released from agonist-stimulated human platelets. Blood 1995; 86 (01) 193-202
• 19 Vogt K, Mahajan-Thakur S, Wolf R. , et al. Release of platelet-derived sphingosine-1-phosphate involves multidrug resistance protein 4 (MRP4/ABCC4) and is inhibited by statins. Thromb Haemost 2018; 118 (01) 132-142
• 20 Vu TM, Ishizu AN, Foo JC. , et al. Mfsd2b is essential for the sphingosine-1-phosphate export in erythrocytes and platelets. Nature 2017; 550 (7677): 524-528
• 21 Moritz E, Wegner D, Groß S. , et al. Reference intervals for serum sphingosine-1-phosphate in the population-based Study of Health in Pomerania. Clin Chim Acta 2017; 468: 25-31
• 22 Winkler MS, Märtz KB, Nierhaus A. , et al. Loss of sphingosine 1-phosphate (S1P) in septic shock is predominantly caused by decreased levels of high-density lipoproteins (HDL). J Intensive Care 2019; 7: 23
• 23 Ostan R, Monti D, Gueresi P, Bussolotto M, Franceschi C, Baggio G. Gender, aging and longevity in humans: an update of an intriguing/neglected scenario paving the way to a gender-specific medicine. Clin Sci (Lond) 2016; 130 (19) 1711-1725
• 24 Mizugishi K, Yamashita T, Olivera A, Miller GF, Spiegel S, Proia RL. Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol 2005; 25 (24) 11113-11121
• 25 Pappu R, Schwab SR, Cornelissen I. , et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 2007; 316 (5822): 295-298
• 26 Hänel P, Andréani P, Gräler MH. Erythrocytes store and release sphingosine 1-phosphate in blood. FASEB J 2007; 21 (04) 1202-1209
• 27 Bode C, Sensken S-C, Peest U. , et al. Erythrocytes serve as a reservoir for cellular and extracellular sphingosine 1-phosphate. J Cell Biochem 2010; 109 (06) 1232-1243
• 28 Fleming JK, Glass TR, Lackie SJ, Wojciak JM. A novel approach for measuring sphingosine-1-phosphate and lysophosphatidic acid binding to carrier proteins using monoclonal antibodies and the kinetic exclusion assay. J Lipid Res 2016; 57 (09) 1737-1747