title: Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis.
abstract: In hereditary hemochromatosis, iron deposition in the liver parenchyma may lead to fibrosis, cirrhosis and hepatocellular carcinoma. Most cases are ascribed to a common mutation in the HFE gene, but the extent of clinical expression is greatly influenced by the combined action of yet unidentified genetic and/or environmental modifying factors. In mice, transcription factor NRF2 is a critical determinant of hepatocyte viability during exposure to acute dietary iron overload. We evaluated if the genetic disruption of Nrf2 would prompt the development of liver damage in Hfe-/-mice (an established model of human HFE-hemochromatosis).
  
  
  
  Wild-type, Nrf2-/-, Hfe-/-and double knockout (Hfe/Nrf2-/-) female mice on C57BL/6 genetic background were sacrificed at the age of 6 (young), 12-18 (middle-aged) or 24 months (old) for evaluation of liver pathology.
  
  
  
  Despite the parenchymal iron accumulation, Hfe-/-mice presented no liver injury. The combination of iron overload (Hfe-/-) and defective antioxidant defences (Nrf2-/-) increased the number of iron-related necroinflammatory lesions (sideronecrosis), possibly due to the accumulation of toxic oxidation products such as 4-hydroxy-2-nonenal-protein adducts. The engulfment of dead hepatocytes led to a gradual accumulation of iron within macrophages, featuring large aggregates. Myofibroblasts recruited towards the injury areas produced substantial amounts of collagen fibers involving the liver parenchyma of double-knockout animals with increased hepatic fibrosis in an age-dependent manner.
  
  
  
  The genetic disruption of Nrf2 promotes the transition from iron accumulation (siderosis) to liver injury in Hfe-/-mice, representing the first demonstration of spontaneous hepatic fibrosis in the long term in a mouse model of hereditary hemochromatosis displaying mildly elevated liver iron.
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Basic & Clinical Research on Iron Biology, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. Electronic address: tduarte@ibmc.up.pt.
authors.forename: Tiago L
authors.initials: TL
authors.lastname: Duarte
authors.affiliation: Iron and Innate Immunity Group, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Carolina
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Basic & Clinical Research on Iron Biology, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Ana G
authors.initials: AG
authors.lastname: Santos
authors.affiliation: Iron and Innate Immunity Group, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Sandro
authors.initials: S
authors.lastname: Silva-Gomes
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Basic & Clinical Research on Iron Biology, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Andreia
authors.initials: A
authors.lastname: Santos-Gonçalves
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Department of Biomedicine, Unit of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Martins
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Basic & Clinical Research on Iron Biology, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal; Centro Hospitalar do Porto-Hospital Santo António, Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
authors.forename: Graça
authors.initials: G
authors.lastname: Porto
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal; Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; Centro Hospitalar de São João, Porto, Portugal.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Lopes
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000071020:Hemochromatosis Protein / Q000235:genetics*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics*
chemical_list: D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D007501:Iron
keywords: Hepatocyte; Iron; Macrophage; Oxidative stress; Sideronecrosis