Journal of Molecular Medicine

, Volume 93, Issue 5, pp 489–498 | Cite as

Hfe and Hjv exhibit overlapping functions for iron signaling to hepcidin

  • Patricia Kent
  • Nicole Wilkinson
  • Marco Constante
  • Carine Fillebeen
  • Konstantinos Gkouvatsos
  • John Wagner
  • Marzell Buffler
  • Christiane Becker
  • Klaus Schümann
  • Manuela M. Santos
  • Kostas PantopoulosEmail author
Original Article


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.

Key messages

  • 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.


Hemochromatosis Iron overload BMP/SMAD 



This work was supported by a grant from the Canadian Institutes for Health Research (MOP-86514). KP and MMS were recipients of Chercheur National and Chercheur Senior career awards, respectively, from the Fonds de la Recherche en Santé du Quebéc (FRSQ). KG was supported by doctoral awards from the J. Latsis and A. Onassis Public Benefit Foundations and from FRSQ.


The authors declare no competing financial interests.

Supplementary material

109_2015_1253_MOESM1_ESM.pdf (493 kb)
ESM 1 (PDF 492 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Patricia Kent
    • 1
  • Nicole Wilkinson
    • 1
  • Marco Constante
    • 1
    • 2
  • Carine Fillebeen
    • 1
  • Konstantinos Gkouvatsos
    • 1
  • John Wagner
    • 1
  • Marzell Buffler
    • 3
  • Christiane Becker
    • 3
  • Klaus Schümann
    • 4
  • Manuela M. Santos
    • 2
  • Kostas Pantopoulos
    • 1
    Email author
  1. 1.Lady Davis Institute for Medical Research, Jewish General Hospital, and Department of MedicineMcGill UniversityMontrealCanada
  2. 2.Centre de Recherche, Centre Hospitalier de l’Université de Montréal (CHUM), and Département de MédecineUniversité de MontréalMontrealCanada
  3. 3.Animal Nutrition UnitTechnische Universität MünchenFreising-WeihenstephanGermany
  4. 4.Molecular Nutrition Unit, Research Center for Nutrition and Food ScienceTechnische Universität MünchenFreising-WeihenstephanGermany

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