title: Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma.
abstract: The IkappaB kinase (IKK) subunit NEMO/IKKgamma is essential for activation of the transcription factor NF-kappaB, which regulates cellular responses to inflammation. The function of NEMO in the adult liver remains elusive. Here we show that ablation of NEMO in liver parenchymal cells caused the spontaneous development of hepatocellular carcinoma in mice. Tumor development was preceded by chronic liver disease resembling human nonalcoholic steatohepatitis (NASH). Antioxidant treatment and genetic ablation of FADD demonstrated that death receptor-mediated and oxidative stress-dependent death of NEMO-deficient hepatocytes triggered disease pathogenesis in this model. These results reveal that NEMO-mediated NF-kappaB activation in hepatocytes has an essential physiological function to prevent the spontaneous development of steatohepatitis and hepatocellular carcinoma, identifying NEMO as a tumor suppressor in the liver.
authors.affiliation: Institute for Genetics, University of Cologne, Zülpicher Strasse 47, 50674 Cologne, Germany.
authors.forename: Tom
authors.initials: T
authors.lastname: Luedde
authors.forename: Naiara
authors.initials: N
authors.lastname: Beraza
authors.forename: Vasileios
authors.initials: V
authors.lastname: Kotsikoris
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
authors.forename: Arianna
authors.initials: A
authors.lastname: Nenci
authors.forename: Rita
authors.initials: R
authors.lastname: De Vos
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
mesh_terms: D000818:Animals; D017209:Apoptosis; D001973:Bromodeoxyuridine; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000502:physiology; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism; D051550:I-kappa B Kinase / Q000502:physiology*; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D016350:Leucine Zippers; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D012333:RNA, Messenger; D025801:Ubiquitin; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D001973:Bromodeoxyuridine