The physiological significance of sphingosine 1-phosphate (S1P) transport in blood has been debated. We have recently reported a comprehensive sphingolipid profile in human plasma and lipoprotein particles (VLDL, LDL, and HDL) using HPLC-MS/MS (Hammad et al., 2010). We now determined the relative concentrations of sphingolipids including S1P in the plasma subfraction containing lipoproteins compared to those in the remaining plasma proteins. Sphingomyelin and ceramide were predominantly recovered in the lipoprotein-containing fraction. Total plasma S1P concentration was positively correlated with S1P concentration in the protein-containing fraction, but not with S1P concentration in the lipoprotein-containing fraction. The percentage of S1P transported in plasma lipoproteins was positively correlated with HDL cholesterol (HDL-C) concentration; however, S1P transport in lipoproteins was not limited by the concentration of HDL-C in the individual subject. Thus, different plasma pools of S1P may have different contributions to S1P signaling in health and disease. 1. Introduction Sphingolipids have been implicated in diseases such as cancer, obesity, and atherosclerosis; however, efforts addressing blood sphingolipids as biomarkers of disease or targets for therapeutics are still in their infancy. Sphingosine-1-phosphate (S1P) is a bioactive lipid that has been shown to play major roles in immunity, inflammation, and cardiovascular physiology [1–6]. S1P is found in plasma at relatively high concentrations (>200？nM) and is transported in blood bound both to lipoproteins (~65%) and albumin [7–9] with the bulk of the lipoprotein-associated S1P found in HDL (~54%), especially the smaller diameter HDL3 subfraction [10, 11]. Plasma HDL cholesterol levels correlate positively with those of plasma S1P [12], but HDLs do not appear to be merely inert carriers of S1P as the S1P constituent of HDL is biologically active and contributes to numerous metabolic effects of HDL [10, 11, 13–16]. We have recently reported a comprehensive sphingolipid profile in “normal” human plasma and lipoprotein particles (VLDL, LDL, and HDL) using HPLC-MS/MS [9]. As an extension of this study we now identify the nonlipoprotein (albumin)-associated versus the lipoprotein-associated sphingolipids. It is established that the concentration of S1P in plasma/serum is much higher than the half-maximal concentration of S1P needed to stimulate its receptors. Nevertheless, it was shown for instance that the inositol phosphate response mediated by S1P receptors was much smaller than the response
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