Adaptive response of iron absorption to anemia, increased erythropoiesis, iron deficiency, and iron loading in beta2-microglobulin knockout mice.
Recently, a novel gene of the major histocompatibility complex (MHC) class I family, HFE (HLA-H), has been found to be mutated in a large proportion of hereditary hemochromatosis (HH) patients. Further support for a causative role of HFE in this disease comes from the observation that beta2-microglobulin knockout (beta2m-/-) mice, that fail to express MHC class I products, develop iron overload. We have now used this animal model of HH to examine the capacity to adapt iron absorption in response to altered iron metabolism in the absence of beta2m-dependent molecule(s). Mucosal uptake, mucosal transfer and retention of iron were measured in control and beta2m-/- mice with altered iron metabolism. Mucosal uptake of Fe(III), but not of Fe(II), by the mutant mice was significantly higher when compared with B6 control mice. Mucosal transfer in the beta2m-/- mice was higher, independent of the iron form tested. No significant differences were found in iron absorption between control and beta2m-/- mice when anemia was induced either by repetitive bleeding or by hemolysis through phenylhydrazine treatment. However, iron absorption in mice made anemic by dietary deprivation of iron was significantly higher in the mutant mice. Furthermore, the beta2m-/- mice manifested an impaired capacity to downmodulate iron absorption when dietary or parenterally iron-loaded. The expression of the defect in iron absorption in the beta2m-/- mice is quantitative, with iron absorption being excessively high for the size of body iron stores. The higher iron absorption capacity in the beta2m-/- mice may involve the initial step of ferric mucosal uptake and the subsequent step of mucosal transfer of iron to the plasma.
Santos
M
M
Department of Immunology, Eijkman-Winkler Institute, University Hospital Utrecht, Utrecht, The Netherlands.
Clevers
H
H
de Sousa
M
M
Marx
J J
JJ
D000222:Adaptation, Physiological; D000818:Animals; D004920:Erythropoiesis / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006680:HLA Antigens / Q000235:genetics; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D000090463:Iron Deficiencies; D019190:Iron Overload / Q000235:genetics*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D001613:beta 2-Microglobulin / Q000172:deficiency* / Q000235:genetics*
D006680:HLA Antigens; D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D001613:beta 2-Microglobulin