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Enhanced erythropoiesis in Hfe-KO mice indicates a role for Hfe in the modulation of erythroid iron homeostasis.
- Source :
-
Blood [Blood] 2011 Jan 27; Vol. 117 (4), pp. 1379-89. Date of Electronic Publication: 2010 Nov 08. - Publication Year :
- 2011
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Abstract
- In hereditary hemochromatosis, mutations in HFE lead to iron overload through abnormally low levels of hepcidin. In addition, HFE potentially modulates cellular iron uptake by interacting with transferrin receptor, a crucial protein during erythropoiesis. However, the role of HFE in this process was never explored. We hypothesize that HFE modulates erythropoiesis by affecting dietary iron absorption and erythroid iron intake. To investigate this, we used Hfe-KO mice in conditions of altered dietary iron and erythropoiesis. We show that Hfe-KO mice can overcome phlebotomy-induced anemia more rapidly than wild-type mice (even when iron loaded). Second, we evaluated mice combining the hemochromatosis and β-thalassemia phenotypes. Our results suggest that lack of Hfe is advantageous in conditions of increased erythropoietic activity because of augmented iron mobilization driven by deficient hepcidin response. Lastly, we demonstrate that Hfe is expressed in erythroid cells and impairs iron uptake, whereas its absence exclusively from the hematopoietic compartment is sufficient to accelerate recovery from phlebotomy. In summary, we demonstrate that Hfe influences erythropoiesis by 2 distinct mechanisms: limiting hepcidin expression under conditions of simultaneous iron overload and stress erythropoiesis, and impairing transferrin-bound iron uptake by erythroid cells. Moreover, our results provide novel suggestions to improve the treatment of hemochromatosis.
- Subjects :
- Aging blood
Aging metabolism
Aging physiology
Animals
Animals, Newborn
Antimicrobial Cationic Peptides genetics
Antimicrobial Cationic Peptides metabolism
Hemochromatosis Protein
Hepcidins
Histocompatibility Antigens Class I metabolism
Histocompatibility Antigens Class I physiology
Homeostasis genetics
Homeostasis physiology
Iron Overload genetics
Iron Overload metabolism
Membrane Proteins metabolism
Membrane Proteins physiology
Mice
Mice, Inbred C57BL
Mice, Knockout
Stress, Physiological genetics
Stress, Physiological physiology
Transferrin metabolism
Up-Regulation genetics
Up-Regulation physiology
Erythroid Cells metabolism
Erythropoiesis genetics
Histocompatibility Antigens Class I genetics
Iron metabolism
Membrane Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 117
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 21059897
- Full Text :
- https://doi.org/10.1182/blood-2010-09-307462