Hepatocyte Caspase-8 is an Essential Modulator of Steatohepatitis in Rodents

In human and murine models of nonalcoholic steatohepatitis (NASH), increased hepatocyte apoptosis is a critical mechanism contributing to inflammation and fibrogenesis. Caspase 8 (Casp8) is essential for death-receptor-mediated apoptosis activity and therefore its modulation might be critical for th...

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Detalhes bibliográficos
Autores: Hatting, Maximilian, Gang, Zhao, Schumacher, Fabienne, Sellge, Gernot, Masaoudi, Malika Al, Gassler, Nikolaus, Boekschoten, Mark, Müller, Michael, Liedtke, Christian, Cubero Palero, Francisco Javier, Trautwein, Christian
Tipo de documento: artigo
Data de publicação:2012
País:España
Recursos:Universidad Complutense de Madrid (UCM)
Repositório:Docta Complutense
Idioma:inglês
OAI Identifier:oai:docta.ucm.es:20.500.14352/98118
Acesso em linha:https://hdl.handle.net/20.500.14352/98118
Access Level:Acceso aberto
Palavra-chave:616.1/.9
Ciencias Biomédicas
Biología
Biología celular (Biología)
Biología molecular (Biología)
Inmunología
24 Ciencias de la Vida
2407 Biología Celular
2415 Biología Molecular
2412 Inmunología
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oai_identifier_str oai:docta.ucm.es:20.500.14352/98118
network_acronym_str ES
network_name_str España
repository_id_str
spelling Hepatocyte Caspase-8 is an Essential Modulator of Steatohepatitis in RodentsHatting, MaximilianGang, ZhaoSchumacher, FabienneSellge, GernotMasaoudi, Malika AlGassler, NikolausBoekschoten, MarkMüller, MichaelLiedtke, ChristianCubero Palero, Francisco JavierTrautwein, Christian616.1/.9Ciencias BiomédicasBiologíaBiología celular (Biología)Biología molecular (Biología)Inmunología24 Ciencias de la Vida2407 Biología Celular2415 Biología Molecular2412 InmunologíaIn human and murine models of nonalcoholic steatohepatitis (NASH), increased hepatocyte apoptosis is a critical mechanism contributing to inflammation and fibrogenesis. Caspase 8 (Casp8) is essential for death-receptor-mediated apoptosis activity and therefore its modulation might be critical for the pathogenesis of NASH. The aim was to dissect the role of hepatocyte Casp8 in a murine model of steatohepatitis. We generated hepatocyte-specific Casp8 knockout (Casp8(Δhep) ) mice. Animals were fed with a methionine-choline-deficient (MCD) diet. Liver injury was assessed by histopathological analysis, apoptotic death, serum alanine aminotransferase (ALT), fluorescent-activated cell sorter (FACS), analysis of liver infiltration and inflammation, reactive oxygen species (ROS), and liver fibrosis. MCD feeding triggered steatosis, hepatic lipid storage, and accumulation of free fatty acid (FFA) in wildtype (WT) livers, which were significantly reduced in Casp8(Δhep) animals. Additionally, lack of Casp8 expression in hepatocytes reduced the MCD-dependent increase in apoptosis and decreased expression of proinflammatory cytokines as well as hepatic infiltration. As a consequence, ROS production was lower, leading to a reduction in the progression of liver fibrosis in Casp8(Δhep) livers. Conclusion: Selective ablation of Casp8 in hepatocytes ameliorates development of NASH by modulating liver injury. Casp8-directed therapy might be a plausible treatment for patients with steatohepatitis. (HEPATOLOGY 2013;57:2189-2201).Lippincott, Williams & WilkinsUniversidad Complutense de Madrid20122012-12-1420122012-12-14journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/98118reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/981182026-06-02T12:44:21Z
dc.title.none.fl_str_mv Hepatocyte Caspase-8 is an Essential Modulator of Steatohepatitis in Rodents
title Hepatocyte Caspase-8 is an Essential Modulator of Steatohepatitis in Rodents
spellingShingle Hepatocyte Caspase-8 is an Essential Modulator of Steatohepatitis in Rodents
Hatting, Maximilian
616.1/.9
Ciencias Biomédicas
Biología
Biología celular (Biología)
Biología molecular (Biología)
Inmunología
24 Ciencias de la Vida
2407 Biología Celular
2415 Biología Molecular
2412 Inmunología
title_short Hepatocyte Caspase-8 is an Essential Modulator of Steatohepatitis in Rodents
title_full Hepatocyte Caspase-8 is an Essential Modulator of Steatohepatitis in Rodents
title_fullStr Hepatocyte Caspase-8 is an Essential Modulator of Steatohepatitis in Rodents
title_full_unstemmed Hepatocyte Caspase-8 is an Essential Modulator of Steatohepatitis in Rodents
title_sort Hepatocyte Caspase-8 is an Essential Modulator of Steatohepatitis in Rodents
dc.creator.none.fl_str_mv Hatting, Maximilian
Gang, Zhao
Schumacher, Fabienne
Sellge, Gernot
Masaoudi, Malika Al
Gassler, Nikolaus
Boekschoten, Mark
Müller, Michael
Liedtke, Christian
Cubero Palero, Francisco Javier
Trautwein, Christian
author Hatting, Maximilian
author_facet Hatting, Maximilian
Gang, Zhao
Schumacher, Fabienne
Sellge, Gernot
Masaoudi, Malika Al
Gassler, Nikolaus
Boekschoten, Mark
Müller, Michael
Liedtke, Christian
Cubero Palero, Francisco Javier
Trautwein, Christian
author_role author
author2 Gang, Zhao
Schumacher, Fabienne
Sellge, Gernot
Masaoudi, Malika Al
Gassler, Nikolaus
Boekschoten, Mark
Müller, Michael
Liedtke, Christian
Cubero Palero, Francisco Javier
Trautwein, Christian
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 616.1/.9
Ciencias Biomédicas
Biología
Biología celular (Biología)
Biología molecular (Biología)
Inmunología
24 Ciencias de la Vida
2407 Biología Celular
2415 Biología Molecular
2412 Inmunología
topic 616.1/.9
Ciencias Biomédicas
Biología
Biología celular (Biología)
Biología molecular (Biología)
Inmunología
24 Ciencias de la Vida
2407 Biología Celular
2415 Biología Molecular
2412 Inmunología
description In human and murine models of nonalcoholic steatohepatitis (NASH), increased hepatocyte apoptosis is a critical mechanism contributing to inflammation and fibrogenesis. Caspase 8 (Casp8) is essential for death-receptor-mediated apoptosis activity and therefore its modulation might be critical for the pathogenesis of NASH. The aim was to dissect the role of hepatocyte Casp8 in a murine model of steatohepatitis. We generated hepatocyte-specific Casp8 knockout (Casp8(Δhep) ) mice. Animals were fed with a methionine-choline-deficient (MCD) diet. Liver injury was assessed by histopathological analysis, apoptotic death, serum alanine aminotransferase (ALT), fluorescent-activated cell sorter (FACS), analysis of liver infiltration and inflammation, reactive oxygen species (ROS), and liver fibrosis. MCD feeding triggered steatosis, hepatic lipid storage, and accumulation of free fatty acid (FFA) in wildtype (WT) livers, which were significantly reduced in Casp8(Δhep) animals. Additionally, lack of Casp8 expression in hepatocytes reduced the MCD-dependent increase in apoptosis and decreased expression of proinflammatory cytokines as well as hepatic infiltration. As a consequence, ROS production was lower, leading to a reduction in the progression of liver fibrosis in Casp8(Δhep) livers. Conclusion: Selective ablation of Casp8 in hepatocytes ameliorates development of NASH by modulating liver injury. Casp8-directed therapy might be a plausible treatment for patients with steatohepatitis. (HEPATOLOGY 2013;57:2189-2201).
publishDate 2012
dc.date.none.fl_str_mv 2012
2012-12-14
2012
2012-12-14
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/98118
url https://hdl.handle.net/20.500.14352/98118
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Lippincott, Williams & Wilkins
publisher.none.fl_str_mv Lippincott, Williams & Wilkins
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.198674

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