Saturated free fatty acid release and intracellular ceramide generation during apoptosis induction are closely related processes.
Apoptosis induced by cells from the immune system is frequently associated with an increase in the ceramide content of target cells, due to the activation of sphingomyelinases (SMase). Some studies have also reported the release of saturated and monounsaturated free fatty acids (FFA) from apoptotic cells. However, the possible relationship between these lipid biochemistry events has not been characterized. We have analysed for the first time the release of FFA triggered by tumor necrosis factor-alpha (TNF-alpha), Fas/CD95 or the perforin/granzyme system of cytotoxic T lymphocytes (CTL) and their relationship to intracellular ceramide generation. TNF-alpha- and Fas-induced apoptosis are associated with both intracellular ceramide generation from sphingomyelin (SM) and release of palmitic-derived FFA, with similar kinetics. Intracellular SMase activation and FFA release from target cells during Fas-induced apoptosis are much more rapid and efficient if Fas-based cytotoxicity is exerted by alloantigenic CTL. In the case of perforin/granzyme-based cytotoxicity exerted by CTL, intracellular ceramide generation and FFA release from target cells seem to depend on the type of lysis induction used. Importantly, the correlation between intracellular SMase activation and the release of palmitic acid-derived FFA from target cells has been observed in all types of cytotoxicity assayed. In addition, exogenous natural ceramide induces the rapid release of the same FFA, well before any apoptotic sign is detected, and FFA release during Fas-induced apoptosis is inhibited in SM-depleted cells by chronic fumonisin-B(1) treatment. These results demonstrate a novel connection between the release of palmitic acid-derived FFA and intracellular ceramide accumulation during apoptosis induction.
Iturralde
María
M
Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, E-50009 Zaragoza, Spain.
Gamen
Susana
S
Pardo
Julián
J
Bosque
Alberto
A
Piñeiro
Andrés
A
Alava
María Angeles
MA
Naval
Javier
J
Anel
Alberto
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002250:Carbon Radioisotopes / Q000378:metabolism; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism*; D004789:Enzyme Activation; D005230:Fatty Acids, Nonesterified / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D019308:Palmitic Acid / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D002250:Carbon Radioisotopes; D002518:Ceramides; D005230:Fatty Acids, Nonesterified; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D019308:Palmitic Acid; D013108:Sphingomyelin Phosphodiesterase