RT Journal Article
T1 Loss of Caspase-8 Protects Mice Against Inflammation-Related Hepatocarcinogenesis but Induces Non-Apoptotic Liver Injury
A1 Liedtke, Christian
A1 Cubero Palero, Francisco Javier
A1 Trautwein, Christian
AB BACKGROUND & AIMS: Disruption of the nuclear factor-kB (NF-kB) essential modulator (NEMO) in hepatocytesof mice (NEMOAhepa mice) results in spontaneous liverapoptosis 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 afterinduction 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 steatosisand hepatocarcinogenesis but had a separate, spontaneous phenotype that included massive liver necrosis, cholestasis, and biliary lesions. The common mechanism by which inactivationof 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 byCasp8, 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-mediatednecrosis in an inflammatory environment.
PB Elsevier
SN 0016-5085
YR 2011
FD 2011-08-28
LK https://hdl.handle.net/20.500.14352/97655
UL https://hdl.handle.net/20.500.14352/97655
LA eng
NO Liedtke 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.
NO *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
NO Instituto de Salud Carlos III
NO Ministerio de Ciencia e Innovación
NO Deutsche Krebshilfe
NO Deutsche Forschungsgemeinschaf
DS Docta Complutense
RD 21 ago 2024