title: Hfe and Hjv exhibit overlapping functions for iron signaling to hepcidin.
abstract: Functional inactivation of HFE or hemojuvelin (HJV) is causatively linked to adult or juvenile hereditary hemochromatosis, respectively. Systemic iron overload results from inadequate expression of hepcidin, the iron regulatory hormone. While HJV regulates hepcidin by amplifying bone morphogenetic protein (BMP) signaling, the role of HFE in the hepcidin pathway remains incompletely understood. We investigated the pathophysiological implications of combined Hfe and Hjv ablation in mice. Isogenic Hfe (-)/(-) and Hjv (-)/(-) mice were crossed to generate double Hfe (-)/(-) Hjv (-)/(-) progeny. Wild-type control and mutant mice of all genotypes were analyzed for serum, hepatic, and splenic iron content, expression of iron metabolism proteins, and expression of hepcidin and Smad signaling in the liver, in response to a standard or an iron-enriched diet. As expected, Hfe (-)/(-) and Hjv (-)/(-) mice developed relatively mild or severe iron overload, respectively, which corresponded to the degree of hepcidin inhibition. The double Hfe (-)/(-) Hjv (-)/(-) mice exhibited an indistinguishable phenotype to single Hjv (-)/(-) counterparts with regard to suppression of hepcidin, serum and hepatic iron overload, splenic iron deficiency, tissue iron metabolism, and Smad signaling, under both dietary regimens. We conclude that the hemochromatotic phenotype caused by disruption of Hjv is not further aggravated by combined Hfe/Hjv deficiency. Our results provide genetic evidence that Hfe and Hjv operate in the same pathway for the regulation of hepcidin expression and iron metabolism.
  
  
  CONCLUSIONS
  Combined disruption of Hfe and Hjv phenocopies single Hjv deficiency. Single Hjv(-)/(-) and double Hfe(-)/(-)Hjv(-)/(-) mice exhibit comparable iron overload. Hfe and Hjv regulate hepcidin via the same pathway.
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, and Department of Medicine, McGill University, Montreal, QC, Canada.
authors.forename: Patricia
authors.initials: P
authors.lastname: Kent
authors.forename: Nicole
authors.initials: N
authors.lastname: Wilkinson
authors.forename: Marco
authors.initials: M
authors.lastname: Constante
authors.forename: Carine
authors.initials: C
authors.lastname: Fillebeen
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Gkouvatsos
authors.forename: John
authors.initials: J
authors.lastname: Wagner
authors.forename: Marzell
authors.initials: M
authors.lastname: Buffler
authors.forename: Christiane
authors.initials: C
authors.lastname: Becker
authors.forename: Klaus
authors.initials: K
authors.lastname: Schümann
authors.forename: Manuela M
authors.initials: MM
authors.lastname: Santos
authors.forename: Kostas
authors.initials: K
authors.lastname: Pantopoulos
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D058851:GPI-Linked Proteins; D015870:Gene Expression; D006432:Hemochromatosis / Q000097:blood / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071020:Hemochromatosis Protein; D064451:Hepcidins / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D007501:Iron / Q000097:blood / Q000378:metabolism*; D019190:Iron Overload / Q000209:etiology / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000378:metabolism / Q000473:pathology
chemical_list: D058851:GPI-Linked Proteins; C504414:HJV protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D051785:Smad Proteins; D007501:Iron