Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice

Junwei Gao, Juxing Chen, Ivana De Domenico, David Koeller, Cary Harding, Robert E. Fleming, Dwight D. Koeberl, Caroline Enns

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Hereditary hemochromatosis is caused by mutations in the hereditary hemochromatosis protein (HFE), transferrinreceptor 2 (TfR2), hemojuvelin, hepcidin, or ferroportin genes. Hepcidin is a key iron regulator, which is secreted by the liver, and decreases serum iron levels by causing the down-regulation of the iron transporter, ferroportin. Mutations in either HFE or TfR2 lower hepcidin levels, implying that both HFE and TfR2 are necessary for regulation of hepcidin expression. In this study, we used a recombinant adeno-associated virus, AAV2/8, for hepatocyte-specific expression of either Hfe or Tfr2 in mice. Expression of Hfe in Hfe-null mice both increased Hfe and hepcidin mRNA and lowered hepatic iron and Tf saturation. Expression of Tfr2 in Tfr2-deficient mice had a similar effect, whereas expression of Hfe in Tfr2-deficient mice or of Tfr2 in Hfe-null mice had no effect on liver or serum iron levels. Expression of Hfe in wild-type mice increased hepcidin mRNA and lowered iron levels. In contrast, expression of Tfr2 had no effect on wild-type mice. These findings suggest that Hfe is limiting in formation of the Hfe/Tfr2 complex that regulates hepcidin expression. In addition, these studies show that the use of recombinant AAV vector to deliver genes is a promising approach for studying physiologic consequences of protein complexes.

Original languageEnglish (US)
Pages (from-to)3374-3381
Number of pages8
JournalBlood
Volume115
Issue number16
DOIs
StatePublished - Apr 22 2010

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Hepcidins
Hepatocytes
Iron
Liver
Genes
Dependovirus
Messenger RNA
Mutation
Hemochromatosis
Serum
Viruses
Proteins
Down-Regulation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice. / Gao, Junwei; Chen, Juxing; De Domenico, Ivana; Koeller, David; Harding, Cary; Fleming, Robert E.; Koeberl, Dwight D.; Enns, Caroline.

In: Blood, Vol. 115, No. 16, 22.04.2010, p. 3374-3381.

Research output: Contribution to journalArticle

Gao, J, Chen, J, De Domenico, I, Koeller, D, Harding, C, Fleming, RE, Koeberl, DD & Enns, C 2010, 'Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice', Blood, vol. 115, no. 16, pp. 3374-3381. https://doi.org/10.1182/blood-2009-09-245209
Gao, Junwei ; Chen, Juxing ; De Domenico, Ivana ; Koeller, David ; Harding, Cary ; Fleming, Robert E. ; Koeberl, Dwight D. ; Enns, Caroline. / Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice. In: Blood. 2010 ; Vol. 115, No. 16. pp. 3374-3381.
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