De novo-synthesized ceramide signals apoptosis in astrocytes via extracellular signal-regulated kinase

Recent observations support the importance of ceramide synthesis de novo in the induction of apoptosis. However, the downstream targets of de novo-syn thesized ceramide are unknown, Here we show that palmitate incorporated int o ceramide and induced apoptotic DNA fragmentation in astrocytes, These eff ects of palmitate were exacerbated when fatty acid breakdown was uncoupled and were not evident in neurons, which show a very low capacity to take up and metabolize palmitate, Palmitate-induced apoptosis of astrocytes was pre vented by L-cycloserine and fumonisin B1, two inhibitors of ceramide synthe sis de novo, and by PD098059, an inhibitor of the extracellular signal-regu lated kinase (ERK) cascade. Accordingly, palmitate activated ERK by a proce ss that was dependent on ceramide synthesis de novo and Raf-1, but independ ent of kinase suppressor of Ras, Other potential targets of ceramide in the control of cell fate, namely, c-Jun amino-terminal kinase, p38 mitogen-act ivated protein kinase, and protein kinase B, were not significantly affecte d in astrocytes exposed to palmitate. Results show that the Raf-1/ERK casca de is the selective downstream target of de novo-synthesized ceramide in th e induction of apoptosis in astrocytes and also highlight the importance of ceramide synthesis de novo in apoptosis of astrocytes, which might have pa thophysiological relevance.-Blazquez, C., Galve-Roperh, I., Guzman, M. De n ovo-synthesized ceramide signals apoptosis in astrocytes via extracellular signal-regulated kinase.