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

中枢神经系统（CNS）中的脂蛋白已被证明参与不依赖于胆固醇转运的神经功能调节以及与脂质代谢相关的神经功能调节。我们最近发现脂蛋白是1-磷酸鞘氨醇（S1 P）的载体，并报道了S1 P相关的HDL可以作为内皮细胞的存活因子。因此，脂蛋白似乎是循环血液中S1 P的载体。据报道，除了S1 P之外，还有多种脂质成分与脂蛋白相关。例如，溶血磷脂酸（LPA）通常以低水平存在于LDL中，其浓度响应于氧化应激而增加。相反，LDL中S1 P的含量在其氧化过程中减少。本研究的目的是确定在神经细胞中脂蛋白诱导的作用是否是由S1 P和LPA与其受体的相互作用引起的。首先，我们研究了血浆HDL对星形胶质细胞功能的影响。结果提示，HDL对星形胶质细胞的某些作用可能是通过细胞表面S1 P受体介导的。其次，我们研究了脂蛋白氧化对S1 P或LPA诱导分化的PC 12细胞突起收缩的影响。氧化剂处理的脂蛋白不引起形状变化。这是由于氧化脂蛋白中LPA的增加，尽管脂蛋白中S1 P的含量减少。此外，我们感兴趣的是S1 P和LPA的合成和释放到细胞外空间的中枢神经系统的调节机制。本实验采用两种敏感性和特异性的生物测定法，分别测定了星形胶质细胞条件培养液中S1P_3和LPA_1的含量。我们发现，S1 P集中在HDL（包括apoE）的组分中，而LPA则聚集在白蛋白的组分中。

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.