Search

Your search keyword '"CASP8 and FADD-Like Apoptosis Regulating Protein deficiency"' showing total 2 results
Start Over Descriptor "CASP8 and FADD-Like Apoptosis Regulating Protein deficiency" Topic chemical and drug induced liver injury
2 results on '"CASP8 and FADD-Like Apoptosis Regulating Protein deficiency"'

1. Increased hepatic fibrosis and JNK2-dependent liver injury in mice exhibiting hepatocyte-specific deletion of cFLIP.

Author

Schattenberg JM, Nagel M, Kim YO, Kohl T, Wörns MA, Zimmermann T, Schad A, Longerich T, Schuppan D, He YW, Galle PR, and Schuchmann M

Subjects
Animals, Apoptosis, CASP8 and FADD-Like Apoptosis Regulating Protein genetics, Carbon Tetrachloride, Caspase 3 metabolism, Caspase 9 metabolism, Chemical and Drug Induced Liver Injury genetics, Chemical and Drug Induced Liver Injury pathology, Disease Models, Animal, Disease Progression, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases metabolism, Genotype, Hepatocytes pathology, Liver pathology, Liver Cirrhosis enzymology, Liver Cirrhosis genetics, Liver Cirrhosis pathology, Male, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase 9 deficiency, Mitogen-Activated Protein Kinase 9 genetics, Phenotype, Phosphorylation, Signal Transduction, Thioacetamide, Time Factors, CASP8 and FADD-Like Apoptosis Regulating Protein deficiency, Chemical and Drug Induced Liver Injury etiology, Hepatocytes enzymology, Liver enzymology, Liver Cirrhosis etiology, Mitogen-Activated Protein Kinase 9 metabolism
Abstract

Chronic liver disease promotes hepatocellular injury involving apoptosis and triggers compensatory regeneration that leads to the activation of quiescent stellate cells in the liver. The deposition of extracellular matrix from activated myofibroblasts promotes hepatic fibrosis and the progression to cirrhosis with deleterious effects on liver physiology. The role of apoptosis signaling pathways in the development of fibrosis remains undefined. The aim of the current study was to determine the involvement of the caspase-8 homologue cellular FLICE-inhibitory protein (cFLIP) during the initiation and progression of fibrosis. Liver injury and fibrosis from carbon tetrachloride (CCl(4)) and thioacetamide (TAA) were examined in mice exhibiting a hepatocyte-specific deletion of cFLIP (flip(-/-)). Acute liver injury from CCl(4) and TAA were enhanced in flip(-/-) mice. This was accompanied by increased activation of caspase-3 and -9, pronounced phosphorylation of JNK, and decreased phosphorylation of Erk. Deletion of the cJun NH(2)-terminal kinase 2 (JNK2) in flip(-/-) mice protected from injury. Hepatic fibrosis was increased at baseline in 12-wk-old flip(-/-) mice, and progression of fibrosis from TAA was accelerated compared with the wild type. In conclusion, deletion of cFLIP in hepatocytes leads to increased fibrosis and accelerated fibrosis progression. This is accompanied by increased injury involving the activation of caspases and JNK2. Thus predisposition to liver injury involving increased hepatocellular apoptosis is a critical mediator of accelerated fibrogenesis, and prevention of liver injury will be a most important measure for patients with chronic liver disease.

Published
2012
Full Text
View/download PDF

2. Ablation of c-FLIP in hepatocytes enhances death-receptor mediated apoptosis and toxic liver injury in vivo.

Author

Schattenberg JM, Zimmermann T, Wörns M, Sprinzl MF, Kreft A, Kohl T, Nagel M, Siebler J, Schulze Bergkamen H, He YW, Galle PR, and Schuchmann M

Subjects
Animals, Anthracenes pharmacology, Apoptosis, CASP8 and FADD-Like Apoptosis Regulating Protein genetics, Caspases metabolism, Concanavalin A toxicity, Female, Galactosamine toxicity, Hepatocytes drug effects, Lipopolysaccharides toxicity, MAP Kinase Signaling System drug effects, Mice, Mice, Knockout, fas Receptor agonists, CASP8 and FADD-Like Apoptosis Regulating Protein deficiency, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury pathology, Hepatocytes metabolism, Hepatocytes pathology, Receptors, Death Domain metabolism
Abstract

Background & Aims: Apoptosis is crucially involved in acute and chronic liver injury, including viral, cholestatic, toxic, and metabolic liver disease. Additionally, dysregulation of apoptosis signaling pathways has been implicated in hepatocarcinogenesis. The most prominent members of the apoptosis-mediating tumor necrosis factor receptor superfamily are the TNF-R1 (CD120a) and the CD95 (Apo-1/Fas) receptor. Although extensively studied, the intracellular signaling events in hepatocytes are only incompletely understood., Methods: To examine the role of the caspase-8 homolog cellular FLICE-inhibitory protein (c-FLIP) in liver injury, we generated mice with hepatocyte specific deletion of c-FLIP. Three models of acute liver injury were employed: the agonistic anti-CD95 antibody Jo2, d-galactosamine and LPS (GalN/LPS), and concanavalin A., Results: Conditional ablation of c-FLIP in hepatocytes augmented liver injury and cell death in all three models of liver injury. CD95- and GalN/LPS-induced liver injury was ameliorated by a pancaspase inhibitor, while ConA-induced injury was unaffected by caspase inhibition. Augmented activation of the MAPK JNK was observed in parallel to liver injury in c-FLIP knockout mice in all injury models; however, inhibition of JNK only affected TNF- and ConA-mediated injury., Conclusions: In summary, c-FLIP is a central regulator of cell death in hepatocytes, involving increased activation of caspases and the MAPK JNK., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Published
2011
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results