Loss of Caspase-8 Protects Mice Against Inflammation-Related Hepatocarcinogenesis but Induces Non-Apoptotic Liver Injury

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dc.contributor.authorLiedtke, Christian
dc.contributor.authorCubero Palero, Francisco Javier
dc.contributor.authorTrautwein, Christian
dc.date.accessioned2024-02-01T12:18:19Z
dc.date.available2024-02-01T12:18:19Z
dc.date.issued2011-08-28
dc.description*Department of Medicine III, University Hospital, Aachen, Germany; ‡Department of Radiology, Justus-Liebig University, Giessen, Germany; §Institute of Pathology, University Hospital Aachen, Germany; and Human Genetics Division, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
dc.description.abstractBACKGROUND & AIMS: Disruption of the nuclear factor-kB (NF-kB) essential modulator (NEMO) in hepatocytesof mice (NEMOAhepa mice) results in spontaneous liver apoptosis and chronic liver disease involving inflammation, steatosis, fibrosis, and development of hepatocellular carcinoma. Activation of caspase-8 (Casp8) initiates death receptor-mediated apoptosis. We investigated the pathogenic role of this protease in NEMOAhepa mice or after induction of acute liver injury. METHODS: We created mice with conditional deletion of Casp8 in hepatocytes (Casp8Ahepa) and Casp8AhepaNEMOAhepa double knockout mice. Acute liver injury was induced by Fas-activating antibodies, lipopolysaccharides, or concanavalin A. Spontaneous hepatocarcinogenesis was monitored by magnetic resonance imaging. RESULTS: Hepatocyte-specific deletion of Casp8 protected mice from induction of apoptosis and liver injury by Fas or lipopolysaccharides but increased necrotic damage and reduced survival times of mice given concanavalin A. Casp8AhepaNEMOAhepa mice were protected against steatosis and hepatocarcinogenesis but had a separate, spontaneous phenotype that included massive liver necrosis, cholestasis, and biliary lesions. The common mechanism by which inactivation of Casp8 induces liver necrosis in both injury models involves the formation of protein complexes that included the adaptor protein Fas-associated protein with death domain and the kinases receptor-interacting protein (RIP) 1 and RIP3—these have been shown to be required for programmed necrosis. We demonstrated that hepatic RIP1 was proteolytically cleaved by Casp8, whereas Casp8 inhibition resulted in accumulation of RIP complexes and subsequent liver necrosis. CONCLUSIONS: Inhibition of Casp8 protects mice from hepatocarcinogenesis following chronic liver injury mediated by apoptosis of hepatocytes but can activate RIP-mediated necrosis in an inflammatory environment.
dc.description.departmentDepto. de Inmunología, Oftalmología y ORL
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.sponsorshipInstituto de Salud Carlos III
dc.description.sponsorshipMinisterio de Ciencia e Innovación
dc.description.sponsorshipDeutsche Krebshilfe
dc.description.sponsorshipDeutsche Forschungsgemeinschaf
dc.description.statuspub
dc.identifier.citationLiedtke C, Bangen JM, Freimuth J, Beraza N, Lambertz D, Cubero FJ, Hatting M, Karlmark KR, Streetz KL, Krombach GA, Tacke F, Gassler N, Riethmacher D, Trautwein C. Loss of caspase-8 protects mice against inflammation-related hepatocarcinogenesis but induces non-apoptotic liver injury. Gastroenterology. 2011 Dec;141(6):2176-87. doi: 10.1053/j.gastro.2011.08.037. Epub 2011 Aug 28. PMID: 21878202.
dc.identifier.doi10.1053/j.gastro.2011.08.037
dc.identifier.issn0016-5085
dc.identifier.officialurlhttps://www.sciencedirect.com/science/article/pii/S0016508511012200?via%3Dihub
dc.identifier.pmid21878202
dc.identifier.relatedurlhttps://pubmed.ncbi.nlm.nih.gov/21878202/
dc.identifier.urihttps://hdl.handle.net/20.500.14352/97655
dc.issue.number6
dc.journal.titleGastroenterology
dc.language.isoeng
dc.page.final2187
dc.page.initial2176
dc.publisherElsevier
dc.relation.projectIDSFB TRR57
dc.relation.projectIDFIS09/02010
dc.relation.projectIDPrograma Ramón y Cajal
dc.rights.accessRightsembargoed access
dc.subject.cdu577
dc.subject.ucmCiencias Biomédicas
dc.subject.ucmBiología
dc.subject.ucmBiología celular (Biología)
dc.subject.ucmBiología molecular (Biología)
dc.subject.ucmInmunología
dc.subject.unesco24 Ciencias de la Vida
dc.subject.unesco2407 Biología Celular
dc.subject.unesco2412 Inmunología
dc.subject.unesco2415 Biología Molecular
dc.titleLoss of Caspase-8 Protects Mice Against Inflammation-Related Hepatocarcinogenesis but Induces Non-Apoptotic Liver Injury
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number141
dspace.entity.typePublication
relation.isAuthorOfPublicationb3877679-0fbd-42e6-8541-1efeb2df768a
relation.isAuthorOfPublication.latestForDiscoveryb3877679-0fbd-42e6-8541-1efeb2df768a
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