title: Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death.
abstract: OBJECTIVE
  The liver, being the major site of iron storage, is particularly exposed to the toxic effects of iron. Transcription factor NRF2 is critical for protecting the liver against disease by activating the transcription of genes encoding detoxification/antioxidant enzymes. We aimed to determine if the NRF2 pathway plays a significant role in the protection against hepatic iron overload.
  
  
  METHODS
  Wild-type and Nrf2(-/-) mouse primary hepatocytes were incubated with ferric ammonium citrate. Wild-type and Nrf2(-/-) mice were fed standard rodent chow or iron-rich diet for 2weeks, with or without daily injection of the antioxidant mito-TEMPOL.
  
  
  RESULTS
  In mouse hepatocytes, iron induced the nuclear translocation of NRF2 and the expression of cytoprotective genes in an NRF2-dependent manner. Moreover, Nrf2(-/-) hepatocytes were highly susceptible to iron-induced cell death. Wild-type and Nrf2(-/-) mice fed iron-rich diet accumulated similar amounts of iron in the liver and were equally able to increase the expression of hepatic hepcidin and ferritin. Nevertheless, in Nrf2-null mice the iron loading resulted in progressive liver injury, ranging from mild confluent necrosis to severe necroinflammatory lesions. Hepatocytic cell death was associated with gross ultrastructural damage to the mitochondria. Notably, liver injury was prevented in iron-fed animals that received mito-TEMPOL.
  
  
  CONCLUSIONS
  NRF2 protects the mouse liver against the toxicity of dietary iron overload by preventing hepatocytic cell death. We identify NRF2 as a potential modifier of liver disease in iron overload pathology and show the beneficial effect of the antioxidant mito-TEMPOL in a mouse model of dietary iron-induced liver injury.
authors.affiliation: Iron and Innate Immunity Group, Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal.
authors.forename: Sandro
authors.initials: S
authors.lastname: Silva-Gomes
authors.affiliation: Iron and Innate Immunity Group, Instituto de Biologia Molecular e Celular (IBMC), 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 (IBMC), Universidade do Porto, Porto, Portugal.
authors.forename: Carolina
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal.
authors.forename: Cátia M
authors.initials: CM
authors.lastname: Silva
authors.affiliation: Iron and Innate Immunity Group, Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal.
authors.forename: João V
authors.initials: JV
authors.lastname: Neves
authors.affiliation: Department of Pathology, Centro Hospitalar de São João, Porto, Portugal.
authors.forename: Joanne
authors.initials: J
authors.lastname: Lopes
authors.affiliation: Department of Pathology, Centro Hospitalar de São João, Porto, Portugal; Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) and Medical Faculty of University of Porto, Porto, Portugal.
authors.forename: Fátima
authors.initials: F
authors.lastname: Carneiro
authors.affiliation: Iron and Innate Immunity Group, Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
authors.forename: Pedro N
authors.initials: PN
authors.lastname: Rodrigues
authors.affiliation: Iron and Innate Immunity Group, Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal. Electronic address: tduarte@ibmc.up.pt.
authors.forename: Tiago L
authors.initials: TL
authors.lastname: Duarte
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019190:Iron Overload / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019266:Iron, Dietary / Q000633:toxicity*; D008099:Liver / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013113:Spin Labels
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D019266:Iron, Dietary; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D013113:Spin Labels; C001803:tempol
keywords: 8-Hydroxy-2′-deoxyguanosine; 8-OHdG; 8-hydroxy-2′-deoxyguanosine; AC; ALT; ARE; AST; Antioxidant; FAC; HH; Hemochromatosis; Hepatocyte; MPT; Mito-TEMPOL; Necrosis; PI; RER; ROS; SER; alanine aminotransferase; ammonium citrate; antioxidant response element; aspartate aminotransferase; ferric ammonium citrate; hOGG1; hereditary hemochromatosis; human 8-hydroxyguanine DNA glycosylase 1; mitochondrial permeability transition; propidium iodide; reactive oxygen species; rough endoplasmic reticulum; smooth endoplasmic reticulum