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Hfe Gene Knock-Out in a Mouse Model of Hereditary Hemochromatosis Affects Bodily Iron Isotope Compositions
Hereditary hemochromatosis is a genetic iron overload disease related to a mutation within the HFE gene that controls the expression of hepcidin, the master regulator of systemic iron metabolism. The natural stable iron isotope composition in whole blood of control subjects is different from that of...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8554230/ https://www.ncbi.nlm.nih.gov/pubmed/34722560 http://dx.doi.org/10.3389/fmed.2021.711822 |
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author | Albalat, Emmanuelle Cavey, Thibault Leroyer, Patricia Ropert, Martine Balter, Vincent Loréal, Olivier |
author_facet | Albalat, Emmanuelle Cavey, Thibault Leroyer, Patricia Ropert, Martine Balter, Vincent Loréal, Olivier |
author_sort | Albalat, Emmanuelle |
collection | PubMed |
description | Hereditary hemochromatosis is a genetic iron overload disease related to a mutation within the HFE gene that controls the expression of hepcidin, the master regulator of systemic iron metabolism. The natural stable iron isotope composition in whole blood of control subjects is different from that of hemochromatosis patients and is sensitive to the amount of total iron removed by the phlebotomy treatment. The use of stable isotopes to unravel the pathological mechanisms of iron overload diseases is promising but hampered by the lack of data in organs involved in the iron metabolism. Here, we use Hfe(−/−) mice, a model of hereditary hemochromatosis, to study the impact of the knock-out on iron isotope compositions of erythrocytes, spleen and liver. Iron concentration increases in liver and red blood cells of Hfe(−/−) mice compared to controls. The iron stable isotope composition also increases in liver and erythrocytes, consistent with a preferential accumulation of iron heavy isotopes in Hfe(−/−) mice. In contrast, no difference in the iron concentration nor isotope composition is observed in spleen of Hfe(−/−) and control mice. Our results in mice suggest that the observed increase of whole blood isotope composition in hemochromatosis human patients does not originate from, but is aggravated by, bloodletting. The subsequent rapid increase of whole blood iron isotope composition of treated hemochromatosis patients is rather due to the release of hepatic heavy isotope-enriched iron than augmented iron dietary absorption. Further research is required to uncover the iron light isotope component that needs to balance the accumulation of hepatic iron heavy isotope, and to better understand the iron isotope fractionation associated to metabolism dysregulation during hereditary hemochromatosis. |
format | Online Article Text |
id | pubmed-8554230 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85542302021-10-30 Hfe Gene Knock-Out in a Mouse Model of Hereditary Hemochromatosis Affects Bodily Iron Isotope Compositions Albalat, Emmanuelle Cavey, Thibault Leroyer, Patricia Ropert, Martine Balter, Vincent Loréal, Olivier Front Med (Lausanne) Medicine Hereditary hemochromatosis is a genetic iron overload disease related to a mutation within the HFE gene that controls the expression of hepcidin, the master regulator of systemic iron metabolism. The natural stable iron isotope composition in whole blood of control subjects is different from that of hemochromatosis patients and is sensitive to the amount of total iron removed by the phlebotomy treatment. The use of stable isotopes to unravel the pathological mechanisms of iron overload diseases is promising but hampered by the lack of data in organs involved in the iron metabolism. Here, we use Hfe(−/−) mice, a model of hereditary hemochromatosis, to study the impact of the knock-out on iron isotope compositions of erythrocytes, spleen and liver. Iron concentration increases in liver and red blood cells of Hfe(−/−) mice compared to controls. The iron stable isotope composition also increases in liver and erythrocytes, consistent with a preferential accumulation of iron heavy isotopes in Hfe(−/−) mice. In contrast, no difference in the iron concentration nor isotope composition is observed in spleen of Hfe(−/−) and control mice. Our results in mice suggest that the observed increase of whole blood isotope composition in hemochromatosis human patients does not originate from, but is aggravated by, bloodletting. The subsequent rapid increase of whole blood iron isotope composition of treated hemochromatosis patients is rather due to the release of hepatic heavy isotope-enriched iron than augmented iron dietary absorption. Further research is required to uncover the iron light isotope component that needs to balance the accumulation of hepatic iron heavy isotope, and to better understand the iron isotope fractionation associated to metabolism dysregulation during hereditary hemochromatosis. Frontiers Media S.A. 2021-10-15 /pmc/articles/PMC8554230/ /pubmed/34722560 http://dx.doi.org/10.3389/fmed.2021.711822 Text en Copyright © 2021 Albalat, Cavey, Leroyer, Ropert, Balter and Loréal. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Medicine Albalat, Emmanuelle Cavey, Thibault Leroyer, Patricia Ropert, Martine Balter, Vincent Loréal, Olivier Hfe Gene Knock-Out in a Mouse Model of Hereditary Hemochromatosis Affects Bodily Iron Isotope Compositions |
title | Hfe Gene Knock-Out in a Mouse Model of Hereditary Hemochromatosis Affects Bodily Iron Isotope Compositions |
title_full | Hfe Gene Knock-Out in a Mouse Model of Hereditary Hemochromatosis Affects Bodily Iron Isotope Compositions |
title_fullStr | Hfe Gene Knock-Out in a Mouse Model of Hereditary Hemochromatosis Affects Bodily Iron Isotope Compositions |
title_full_unstemmed | Hfe Gene Knock-Out in a Mouse Model of Hereditary Hemochromatosis Affects Bodily Iron Isotope Compositions |
title_short | Hfe Gene Knock-Out in a Mouse Model of Hereditary Hemochromatosis Affects Bodily Iron Isotope Compositions |
title_sort | hfe gene knock-out in a mouse model of hereditary hemochromatosis affects bodily iron isotope compositions |
topic | Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8554230/ https://www.ncbi.nlm.nih.gov/pubmed/34722560 http://dx.doi.org/10.3389/fmed.2021.711822 |
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