title: Disruption of hemochromatosis protein and transferrin receptor 2 causes iron-induced liver injury in mice.
abstract: Mutations in hemochromatosis protein (HFE) or transferrin receptor 2 (TFR2) cause hereditary hemochromatosis (HH) by impeding production of the liver iron-regulatory hormone, hepcidin (HAMP). This study examined the effects of disruption of Hfe or Tfr2, either alone or together, on liver iron loading and injury in mouse models of HH. Iron status was determined in Hfe knockout (Hfe(-/-)), Tfr2 Y245X mutant (Tfr2(mut)), and double-mutant (Hfe(-/-) ×Tfr2(mut) ) mice by measuring plasma and liver iron levels. Plasma alanine transaminase (ALT) activity, liver histology, and collagen deposition were evaluated to assess liver injury. Hepatic oxidative stress was assessed by measuring superoxide dismutase (SOD) activity and F(2)-isoprostane levels. Gene expression was measured by real-time polymerase chain reaction. Hfe(-/-) ×Tfr2(mut) mice had elevated hepatic iron with a periportal distribution and increased plasma iron, transferrin saturation, and non-transferrin-bound iron, compared with Hfe(-/-), Tfr2(mut), and wild-type (WT) mice. Hamp1 expression was reduced to 40% (Hfe(-/-) and Tfr2(mut) ) and 1% (Hfe(-/-) ×Tfr2(mut)) of WT values. Hfe(-/-) ×Tfr2(mut) mice had elevated plasma ALT activity and mild hepatic inflammation with scattered aggregates of infiltrating inflammatory cluster of differentiation 45 (CD45)-positive cells. Increased hepatic hydoxyproline levels as well as Sirius red and Masson's Trichrome staining demonstrated advanced portal collagen deposition. Hfe(-/-) and Tfr2(mut) mice had less hepatic inflammation and collagen deposition. Liver F(2) -isoprostane levels were elevated, and copper/zinc and manganese SOD activities decreased in Hfe(-/-) ×Tfr2(mut), Tfr2(mut), and Hfe(-/-) mice, compared with WT mice.
  
  
  CONCLUSIONS
  Disruption of both Hfe and Tfr2 caused more severe hepatic iron overload with more advanced lipid peroxidation, inflammation, and portal fibrosis than was observed with the disruption of either gene alone. The Hfe(-/-) ×Tfr2(mut) mouse model of iron-induced liver injury reflects the liver injury phenotype observed in human HH.
authors.affiliation: School of Medicine and Pharmacology, Fremantle Hospital, University of Western Australia, Fremantle, Western Australia, Australia.
authors.forename: Roheeth D
authors.initials: RD
authors.lastname: Delima
authors.forename: Anita C G
authors.initials: AC
authors.lastname: Chua
authors.forename: Janina E E
authors.initials: JE
authors.lastname: Tirnitz-Parker
authors.forename: Eng K
authors.initials: EK
authors.lastname: Gan
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Croft
authors.forename: Ross M
authors.initials: RM
authors.lastname: Graham
authors.forename: John K
authors.initials: JK
authors.lastname: Olynyk
authors.forename: Debbie
authors.initials: D
authors.lastname: Trinder
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression / Q000502:physiology; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D007501:Iron / Q000097:blood; D019190:Iron Overload / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000473:pathology / Q000502:physiology; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D010641:Phenotype; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*
chemical_list: D023181:Antimicrobial Cationic Peptides; C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D008565:Membrane Proteins; D011990:Receptors, Transferrin; C503641:TFR2 protein, mouse; D003094:Collagen; D007501:Iron; D000410:Alanine Transaminase