Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice

This study addressed the contribution of acidic sphingomyelinase (ASMase) in TNF-alpha-mediated hepatocellular apoptosis. Cultured hepatocytes depleted of mitochondrial glutathione (mGSH) became sensitive to TNF-alpha, undergoing a time-dependent apoptotic cell death preceded by mitochondrial membra...

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Autores: García Ruiz, Carmen, Colell Riera, Anna, Marí García, Montserrat, Morales Muñoz, Albert, Calvo Ademuz, Maria, Enrich Bastús, Carles, Fernández-Checa Torres, José Carlos
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2003
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/8312
Acesso em linha:https://hdl.handle.net/2445/8312
Access Level:acceso abierto
Palavra-chave:Apoptosi
Cèl·lules hepàtiques
Medicaments
Apoptosis
Hepatocytes
Liver drug effects
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spelling Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout miceGarcía Ruiz, CarmenColell Riera, AnnaMarí García, MontserratMorales Muñoz, AlbertCalvo Ademuz, MariaEnrich Bastús, CarlesFernández-Checa Torres, José CarlosApoptosiCèl·lules hepàtiquesMedicamentsApoptosisHepatocytesLiver drug effectsThis study addressed the contribution of acidic sphingomyelinase (ASMase) in TNF-alpha-mediated hepatocellular apoptosis. Cultured hepatocytes depleted of mitochondrial glutathione (mGSH) became sensitive to TNF-alpha, undergoing a time-dependent apoptotic cell death preceded by mitochondrial membrane depolarization, cytochrome c release, and caspase activation. Cyclosporin A treatment rescued mGSH-depleted hepatocytes from TNF-alpha-induced cell death. In contrast, mGSH-depleted hepatocytes deficient in ASMase were resistant to TNF-alpha-mediated cell death but sensitive to exogenous ASMase. Furthermore, although in vivo administration of TNF-alpha or LPS to galactosamine-pretreated ASMase(+/+) mice caused liver damage, ASMase(-/-) mice exhibited minimal hepatocellular injury. To analyze the requirement of ASMase, we assessed the effect of glucosylceramide synthetase inhibition on TNF-alpha-mediated apoptosis. This approach, which blunted glycosphingolipid generation by TNF-alpha, protected mGSH-depleted ASMase(+/+) hepatocytes from TNF-alpha despite enhancement of TNF-alpha-stimulated ceramide formation. To further test the involvement of glycosphingolipids, we focused on ganglioside GD3 (GD3) because of its emerging role in apoptosis through interaction with mitochondria. Analysis of the cellular redistribution of GD3 by laser scanning confocal microscopy revealed the targeting of GD3 to mitochondria in ASMase(+/+) but not in ASMase(-/-) hepatocytes. However, treatment of ASMase(-/-) hepatocytes with exogenous ASMase induced the colocalization of GD3 and mitochondria. Thus, ASMase contributes to TNF-alpha-induced hepatocellular apoptosis by promoting the mitochondrial targeting of glycosphingolipids.American Society for Clinical Investigation2003info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/8312Articles publicats en revistes (Biomedicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a http://dx.doi.org/10.1172/JCI200316010The Journal of Clinical Investigation, 2003, vol. 111, núm. 2, p. 197-208.http://dx.doi.org/10.1172/JCI200316010(c) The American Society for Clinical Investigation, 2003info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/83122026-05-27T06:46:51Z
dc.title.none.fl_str_mv Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice
title Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice
spellingShingle Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice
García Ruiz, Carmen
Apoptosi
Cèl·lules hepàtiques
Medicaments
Apoptosis
Hepatocytes
Liver drug effects
title_short Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice
title_full Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice
title_fullStr Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice
title_full_unstemmed Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice
title_sort Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice
dc.creator.none.fl_str_mv García Ruiz, Carmen
Colell Riera, Anna
Marí García, Montserrat
Morales Muñoz, Albert
Calvo Ademuz, Maria
Enrich Bastús, Carles
Fernández-Checa Torres, José Carlos
author García Ruiz, Carmen
author_facet García Ruiz, Carmen
Colell Riera, Anna
Marí García, Montserrat
Morales Muñoz, Albert
Calvo Ademuz, Maria
Enrich Bastús, Carles
Fernández-Checa Torres, José Carlos
author_role author
author2 Colell Riera, Anna
Marí García, Montserrat
Morales Muñoz, Albert
Calvo Ademuz, Maria
Enrich Bastús, Carles
Fernández-Checa Torres, José Carlos
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Apoptosi
Cèl·lules hepàtiques
Medicaments
Apoptosis
Hepatocytes
Liver drug effects
topic Apoptosi
Cèl·lules hepàtiques
Medicaments
Apoptosis
Hepatocytes
Liver drug effects
description This study addressed the contribution of acidic sphingomyelinase (ASMase) in TNF-alpha-mediated hepatocellular apoptosis. Cultured hepatocytes depleted of mitochondrial glutathione (mGSH) became sensitive to TNF-alpha, undergoing a time-dependent apoptotic cell death preceded by mitochondrial membrane depolarization, cytochrome c release, and caspase activation. Cyclosporin A treatment rescued mGSH-depleted hepatocytes from TNF-alpha-induced cell death. In contrast, mGSH-depleted hepatocytes deficient in ASMase were resistant to TNF-alpha-mediated cell death but sensitive to exogenous ASMase. Furthermore, although in vivo administration of TNF-alpha or LPS to galactosamine-pretreated ASMase(+/+) mice caused liver damage, ASMase(-/-) mice exhibited minimal hepatocellular injury. To analyze the requirement of ASMase, we assessed the effect of glucosylceramide synthetase inhibition on TNF-alpha-mediated apoptosis. This approach, which blunted glycosphingolipid generation by TNF-alpha, protected mGSH-depleted ASMase(+/+) hepatocytes from TNF-alpha despite enhancement of TNF-alpha-stimulated ceramide formation. To further test the involvement of glycosphingolipids, we focused on ganglioside GD3 (GD3) because of its emerging role in apoptosis through interaction with mitochondria. Analysis of the cellular redistribution of GD3 by laser scanning confocal microscopy revealed the targeting of GD3 to mitochondria in ASMase(+/+) but not in ASMase(-/-) hepatocytes. However, treatment of ASMase(-/-) hepatocytes with exogenous ASMase induced the colocalization of GD3 and mitochondria. Thus, ASMase contributes to TNF-alpha-induced hepatocellular apoptosis by promoting the mitochondrial targeting of glycosphingolipids.
publishDate 2003
dc.date.none.fl_str_mv 2003
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/8312
url https://hdl.handle.net/2445/8312
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a http://dx.doi.org/10.1172/JCI200316010
The Journal of Clinical Investigation, 2003, vol. 111, núm. 2, p. 197-208.
http://dx.doi.org/10.1172/JCI200316010
dc.rights.none.fl_str_mv (c) The American Society for Clinical Investigation, 2003
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) The American Society for Clinical Investigation, 2003
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Society for Clinical Investigation
publisher.none.fl_str_mv American Society for Clinical Investigation
dc.source.none.fl_str_mv Articles publicats en revistes (Biomedicina)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,198674

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