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

1-磷酸鞘氨醇(S1P)在血浆中积聚在脂蛋白中，尤其是高密度脂蛋白(HDL)中。然而，细胞外S1P是如何在中枢神经系统中产生的，目前还不清楚。本研究的目的是确定星形胶质细胞释放S1P是否与脂蛋白的形成有关。首先，我们证明了人脑脊液中的S1P积聚在高分子量颗粒中，这些颗粒与血浆一样，在富含apoE的高密度脂蛋白组分中分解。S1P受体拮抗剂对人脑脊液高密度脂蛋白诱导的星形胶质细胞迁移反应的抑制作用表明，S1P相关脂蛋白可能通过其受体发挥自分泌和旁分泌作用。其次，我们确定S1P是从星形胶质细胞释放出来的，与脂蛋白的合成是协调的。我们发现S1P在神经鞘氨醇存在的情况下在大鼠和小鼠星形胶质细胞中积聚，并在维甲酸和二丁酰cAMP激活与脂蛋白合成相关的apoE和ABC转运体A1(ABCA1)的表达时其释放增加。星形胶质细胞释放的S1P再次出现在高密度脂蛋白组分中，并可由ABCA1介导，这得到了对ABCA1特异的siRNA、ABCA1-/-小鼠的星形胶质细胞和ABCA1的抑制剂Glybeneclamide的实验结果的支持。这些结果表明，星形胶质细胞通过ABCA1释放S1P与脂蛋白合成有关。

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.