title: NF-κB essential modifier is required for hepatocyte proliferation and the oval cell reaction after partial hepatectomy in mice.
abstract: OBJECTIVE
  The transcription factor nuclear factor κB (NF-κB) is activated by the IκB kinase complex. The regulatory subunit of this complex, NF-κB essential modifier (NEMO or IKBKG), is a tumor suppressor. Hepatocyte-specific deletion of NEMO induces chronic liver inflammation that leads to apoptosis, oxidative stress, development of nonalcoholic steatohepatitis, and hepatocarcinogenesis.
  
  
  METHODS
  We performed partial hepatectomies in mice with hepatocyte-specific disruption of NEMO (Nemo(Δhepa)). Some mice were fed a diet that contained the antioxidant butylated hydroxyanisole (BHA), and others were given daily intraperitoneal injections of the oxidant phenetyl isothiocyanate (PEITC).
  
  
  RESULTS
  Nemo(Δhepa) mice had impaired liver regeneration after partial hepatectomy and 50% mortality, indicating that NEMO is required for the regenerative response. Liver cells of the mice had a strong oxidative stress response; these cells down-regulated the NF-κB-dependent antioxidant response and reduced levels of proteins that repair DNA double-strand breaks. However, the impairments to hepatocyte proliferation were compensated by a response of oval cells in Nemo(Δhepa) mice. Oval cells expressed low levels of albumin and thereby expressed normal levels of NEMO. Repopulation of the liver with oval cells that expressed NEMO reversed liver damage in Nemo(Δhepa) mice. Interestingly, these mice still developed hepatocellular carcinomas 6 months after partial hepatectomy, whereas Nemo(Δhepa) mice fed the BHA diet were protected from carcinogenesis.
  
  
  CONCLUSIONS
  In livers of mice, expression of NEMO and activation of NF-κB are required for hepatocyte proliferation and liver regeneration. These mechanisms require control of oxidative stress and DNA integrity.
authors.affiliation: Department of Internal Medicine, University Hospital (RWTH), Aachen, Germany.
authors.forename: Yann
authors.initials: Y
authors.lastname: Malato
authors.forename: Haksier
authors.initials: H
authors.lastname: Ehedego
authors.forename: Malika
authors.initials: M
authors.lastname: Al-Masaoudi
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Cubero
authors.forename: Jörn
authors.initials: J
authors.lastname: Bornemann
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.forename: Christian
authors.initials: C
authors.lastname: Liedtke
authors.forename: Naiara
authors.initials: N
authors.lastname: Beraza
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology; D002083:Butylated Hydroxyanisole / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000502:physiology* / Q000601:surgery*; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D010641:Phenotype
chemical_list: D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D002083:Butylated Hydroxyanisole