title: Saturated free fatty acid release and intracellular ceramide generation during apoptosis induction are closely related processes.
abstract: 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.
authors.affiliation: Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, E-50009 Zaragoza, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Iturralde
authors.forename: Susana
authors.initials: S
authors.lastname: Gamen
authors.forename: Julián
authors.initials: J
authors.lastname: Pardo
authors.forename: Alberto
authors.initials: A
authors.lastname: Bosque
authors.forename: Andrés
authors.initials: A
authors.lastname: Piñeiro
authors.forename: María Angeles
authors.initials: MA
authors.lastname: Alava
authors.forename: Javier
authors.initials: J
authors.lastname: Naval
authors.forename: Alberto
authors.initials: A
authors.lastname: Anel
mesh_terms: 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
chemical_list: D002250:Carbon Radioisotopes; D002518:Ceramides; D005230:Fatty Acids, Nonesterified; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D019308:Palmitic Acid; D013108:Sphingomyelin Phosphodiesterase