HJV and HFE play distinct roles in regulating hepcidin

Qian Wu, Hao Wang, Peng An, Yunlong Tao, Jiali Deng, Zhuzhen Zhang, Yuanyuan Shen, Caiyong Chen, Junxia Min, Fudi Wang

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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. Innovation: 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. Antioxid. Redox Signal. 22, 1325-1336.

Original languageEnglish (US)
Pages (from-to)1325-1336
Number of pages12
JournalAntioxidants and Redox Signaling
Issue number15
StatePublished - May 20 2015
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry
  • Physiology
  • Clinical Biochemistry
  • Cell Biology


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