title: HJV and HFE Play Distinct Roles in Regulating Hepcidin.
abstract: OBJECTIVE
  Hereditary hemochromatosis (HH) is an iron overload disease that is caused by mutations in HFE, HJV, and several other genes. However, whether HFE-HH and HJV-HH share a common pathway via hepcidin regulation is currently unclear. Recently, some HH patients have been reported to carry concurrent mutations in both the HFE and HJV genes. To dissect the roles and molecular mechanisms of HFE and/or HJV in the pathogenesis of HH, we studied Hfe(-/-), Hjv(-/-), and Hfe(-/-)Hjv(-/-) double-knockout mouse models.
  
  
  RESULTS
  Hfe(-/-)Hjv(-/-) mice developed iron overload in multiple organs at levels comparable to Hjv(-/-) mice. After an acute delivery of iron, the expression of hepcidin (i.e., Hamp1 mRNA) was increased in the livers of wild-type and Hfe(-/-) mice, but not in either Hjv(-/-) or Hfe(-/-)Hjv(-/-) mice. Furthermore, iron-induced phosphorylation of Smad1/5/8 was not detected in the livers of Hjv(-/-) or Hfe(-/-)Hjv(-/-) mice.
  
  
  METHODS
  We generated and phenotypically characterized Hfe(-/-)Hjv(-/-) double-knockout mice. In addition, because they faithfully phenocopy clinical HH patients, these mouse models are an invaluable tool for mechanistically dissecting how HFE and HJV regulate hepcidin expression.
  
  
  CONCLUSIONS
  Based on our results, we conclude that HFE may depend on HJV for transferrin-dependent hepcidin regulation. The presence of residual hepcidin in the absence of HFE suggests either the presence of an unknown regulator (e.g., TFR2) that is synergistic with HJV or that HJV is sufficient to maintain basal levels of hepcidin.
authors.affiliation: 1 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences , Shanghai, China .
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: An
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Tao
authors.forename: Jiali
authors.initials: J
authors.lastname: Deng
authors.forename: Zhuzhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Shen
authors.forename: Caiyong
authors.initials: C
authors.lastname: Chen
authors.forename: Junxia
authors.initials: J
authors.lastname: Min
authors.forename: Fudi
authors.initials: F
authors.lastname: Wang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000071020:Hemochromatosis Protein; D064451:Hepcidins / Q000235:genetics / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000008:administration & dosage* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction
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; D007501:Iron