Regulation of iron absorption in Hfe mutant mice.
Hereditary hemochromatosis is most commonly caused by homozygosity for a point mutation (C282Y) in the human hemochromatosis gene (HFE). The mechanism by which HFE regulates iron absorption is not known, but the C282Y mutation results in loss of cell surface expression of the human hemachromatosis protein (HFE) and hyperabsorption of iron by the duodenal enterocyte. Mice homozygous for a deletion in the mouse hemochromatosis gene (Hfe) or a mutation equivalent to that seen in human hereditary hemochromatosis (C282Y) were compared with wild-type animals for their ability to regulate iron absorption. Both mutant strains hyperabsorbed (59)Fe administered by gavage. Feeding a diet supplemented with carbonyl iron resulted in a more than 5-fold reduction of (59)Fe absorption in both wild-type and mutant mouse strains. Similarly, the iron loading associated with age in Hfe mutant mice resulted in nearly a 4-fold reduction in iron absorption. When mice were stimulated to absorb iron either by depleting iron stores or by inducing erythropoiesis, wild type and Hfe mutant strains increased absorption to similar levels, approximately 5-fold over control values. Our data indicate that Hfe mutant mice retain the ability to regulate iron absorption. Mouse hemachromatosis protein (Hfe) plays a minor role in down-regulation but does not influence the up-regulation of iron absorption.
Ajioka
Richard S
RS
Division of Hematology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City 84132, USA. richard.aijoka@hsc.utah.edu
Levy
Joanne E
JE
Andrews
Nancy C
NC
Kushner
James P
JP
D000375:Aging; D000818:Animals; D004032:Diet; D004909:Erythrocyte Indices; D004920:Erythropoiesis / Q000187:drug effects; D006680:HLA Antigens / Q000235:genetics* / Q000502:physiology*; D006400:Hematocrit; D006432:Hemochromatosis / Q000235:genetics; D000071020:Hemochromatosis Protein; D006454:Hemoglobins / Q000032:analysis; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000502:physiology*; D006706:Homeostasis; D007408:Intestinal Absorption / Q000235:genetics*; D007501:Iron / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007504:Iron Radioisotopes / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D010659:Phenylhydrazines / Q000494:pharmacology; D018962:Phlebotomy; D017701:Reticulocyte Count; D014168:Transferrin / Q000378:metabolism
D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D006454:Hemoglobins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D007504:Iron Radioisotopes; D008565:Membrane Proteins; D010659:Phenylhydrazines; D014168:Transferrin; C030299:phenylhydrazine; D007501:Iron