title: A20 prevents chronic liver inflammation and cancer by protecting hepatocytes from death.
abstract: An important regulator of inflammatory signalling is the ubiquitin-editing protein A20 that acts as a break on nuclear factor-κB (NF-κB) activation, but also exerts important cytoprotective functions. A20 knockout mice are cachectic and die prematurely due to excessive multi-organ inflammation. To establish the importance of A20 in liver homeostasis and pathology, we developed a novel mouse line lacking A20 specifically in liver parenchymal cells. These mice spontaneously develop chronic liver inflammation but no fibrosis or hepatocellular carcinomas, illustrating an important role for A20 in normal liver tissue homeostasis. Hepatocyte-specific A20 knockout mice show sustained NF-κB-dependent gene expression in the liver upon tumor necrosis factor (TNF) or lipopolysaccharide injection, as well as hepatocyte apoptosis and lethality upon challenge with sublethal doses of TNF, demonstrating an essential role for A20 in the protection of mice against acute liver failure. Finally, chronic liver inflammation and enhanced hepatocyte apoptosis in hepatocyte-specific A20 knockout mice was associated with increased susceptibility to chemically or high fat-diet-induced hepatocellular carcinoma development. Together, these studies establish A20 as a crucial hepatoprotective factor.
authors.affiliation: Inflammation Research Center, VIB, Ghent B-9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Catrysse
authors.affiliation: Inflammation Research Center, VIB, Ghent B-9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Farhang Ghahremani
authors.affiliation: Inflammation Research Center, VIB, Ghent B-9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Vereecke
authors.affiliation: Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht NL-3584, The Netherlands.
authors.forename: S A
authors.initials: SA
authors.lastname: Youssef
authors.affiliation: Inflammation Research Center, VIB, Ghent B-9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Mc Guire
authors.affiliation: Inflammation Research Center, VIB, Ghent B-9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Sze
authors.affiliation: Institute of Surgical Pathology, University Zurich, Zurich CH-8091, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Weber
authors.affiliation: Institute of Virology, Technische Universität München, Munich D-81675, Germany.|Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg D-69120, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht NL-3584, The Netherlands.|University Medical Center Groningen, Department of Pediatrics, University of Groningen, Groningen NL-9713, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: de Bruin
authors.affiliation: Inflammation Research Center, VIB, Ghent B-9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Beyaert
authors.affiliation: Inflammation Research Center, VIB, Ghent B-9052, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent B-9052, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: van Loo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D059305:Diet, High-Fat; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D017353:Gene Deletion; D006505:Hepatitis / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000172:deficiency / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; C513261:Tnfaip3 protein, mouse