Ceramide in primary astrocytes from cerebellum: metabolism and role in cell proliferation.

Cerebellar astrocytes are equipped with an efficient molecular machinery able to control the levels, and possibly the subcellular location, of ceramide. The major metabolic routes that contribute to the maintenance and variation of the cellular ceramide include ceramide biosynthesis, by de novo pathway or sphingosine recycling, ceramide formation from complex sphingolipids degradation and ceramide catabolism. In cerebellar astrocytes from rat cerebellum a peculiar metabolism of sphingomyelin occurs. This includes the preponderance of acidic sphingomyelinase, paralleled by a deficiency of the neutral Mg2+-dependent enzyme, as well as the presence of an extra-Golgi form of sphingomyelin synthase, which shares many characteristics with PC-PLC. Moreover these cells are characterized by a high efficiency in converting sphingosine to ceramide, possibly functional to the role played by astrocytes in the prevention of neuronal damage by high sphingosine concentration. Recent evidence demonstrates that a change of ceramide level is one of the key steps in the chain of reactions elicited by mitogenic stimuli. In fact, low cellular levels of ceramide characterize, and appear to be required for, the proliferation of cerebellar astrocytes. In particular mitogenic stimuli, such as basic fibroblast growth factor (bFGF), rapidly down regulate the cellular levels of ceramide by stimulating sphingomyelin synthase. Ceramide acts as an intracellular physiological inhibitor of cell growth, being able to counteract the effect of bFGF by inhibiting the MAP kinase pathway. Although many questions remain in this field, the present knowledge strongly supports that ceramide represents a crucial member within lipid mediators, involved in the signaling pathways underlying cell proliferation in cerebellar astrocytes.