Assessment of the role of sphingosine 1-phosphate and its receptors in high-density lipoprotein-induced stimulation of astroglial cell function

It has been suggested that lipoproteins in the central nervous system are involved in the regulation of several neural functions independent of cholesterol metabolism as well as those related to lipid metabolism. We recently demonstrated that lipoproteins are carriers for sphingosine I-phosphate (SIP). This raised the possibility that S I P mediates the neural cell functions induced by lipoproteins. In the current study, we examined the effects of plasma high-density lipoprotein (HDL) on astroglial cell functions, focusing especially on the role of the lipoprotein-associated S I P. In rat type I astrocytes or C6 glioma cells, similar to S I P, HDL stimulated DNA synthesis and mRNA expression of fibroblast growth factor-2, a potent neurotrophic factor, which was associated with the activation of extracellular signal-regulated kinase (ERK) in a pertussis toxin-sensitive manner. The data from fractionation studies of HDL indicated that S I P may be a major component for the activation of ERK. In C6 glioma cells, HDL also induced phospholipase C-dependent intracellular Ca2+ mobilization. Desensitization of the C6 glioma cells with SIP abolished these HDL-induced actions. Furthermore, overexpression of S I P receptors in C6 glioma cells led to a significant enhancement of HDL-induced ERK activation and Ca2+ mobilization. Thus, at least some HDL-induced actions may be mediated by cell-surface SIP receptors in astroglial cells. These results imply that SIP might partially mediate lipoprotein-induced cholesterol metabolism-independent neural cell functions in the central nervous system.