Coupling of sphingosine 1-phosphate release with lipoprotein formation in central nervous system(CNS)

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Sphingosine 1-phosphate (S1P) is accumulated in lipoproteins, especially high-density lipoprotein (HDL), in plasma. However, it remains uncharacterized how extracellular S1P is produced in the central nervous system. The aim of this study is to establish whether the S1P release from astroglial cells is coupled with lipoprotein formation. First, we demonstrated that S1P in human CSF is accumulated in high molecular weight particles that are resolved in the apoE-rich HDL fraction as was the case for plasma. The ability of S1P receptor antagonist to inhibit the migration response of astrocytes induced by HDL-like lipoproteins from human CSF indicates that S1P-associated lipoproteins may function as autocrine and paracrine factors through their receptors in CNS. Secondly, we determined that S1P is released from astroglial cells in coordination with lipoprotein synthesis. We found that S1P is accumulated in rat and mouse astrocytes in the presence of sphingosine, and its release is increased in response to retinoic acid and dibutyryl cAMP, which activate the expression of apoE and ABC transporter A1 (ABCA1) related to lipoprotein synthesis. The released S1P from astrocytes is present again in the HDL fractions, and can be mediated by ABCA1, which is supported by the results from experiments with siRNAs specific to ABCA1, astrocytes from Abca1-/- mice, and glybeneclamide, an inhibitor of ABCA1. These results suggest that S1P is released in association with lipoprotein synthesis through ABCA1 in astroglial cells.