Sphingosine 1-phosphate mediates some actions of lipoproteins that regulate neural functions.

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Lipoproteins in the central nervous system (CNS) have been shown to participate in the regulation of neural functions independent of cholesterol transport as well as those related to lipid metabolism. We recently discovered that lipoproteins are carriers for sphingosine 1-phosphate (S1P), and reported that the S1P-associated HDL could act as a survival factor in endothelial cells. Thus, lipoproteins seem to serve as carriers for S1P in circulating blood. It has been reported that besides S1P, there are many kinds of lipid components in association with lipoproteins. For example, lysophosphatidic acid (LPA) is usually present in LDL at a low level, its concentration increases in response to oxidative stress. In contrast, the content of S1P in LDL is reduced during its oxidation. The aim of this study was to establish whether in neural cells lipoprotein-induced actions are caused by the interaction of S1P and LPA with their receptors. First, we examined the effects of plasma HDL on astroglial cell functions. The results indicated that some HDL-induced actions might be mediated by cell-surface S1P receptors in astroglial cells. Secondly, we investigated the effect of oxidation of lipoproteins on S1P-or LPA-induced neurite retraction in differentiated PC12 cells. The shape change was not induced by lipoproteins treated with oxidants. This was due to increase of LPA in oxidized lipoproteins, although the content of S1P in lipoproteins was reduced. Furthermore, we were interested in the regulatory mechanisms of S1P and LPA synthesis and their release into extracellular space of the CNS. By using two sensitive and specific bioassays based on the ability to stimulate S1P_3 or LPA_1, we measured the content of S1P and LPA in the conditioned medium of astroglial cells. We found that S1P was concentrated in the fraction of HDL including apoE, while LPA was accumulated in the fraction of albumin.