Duodenal HFE expression and hepcidin levels determine body iron homeostasis: modulation by genetic diversity and dietary iron availability.
HFE affects the interaction of transferrin bound iron with transferrin receptors (TfR) thereby modulating iron uptake. To study genetically determined differences in HFE expression we examined individual HFE levels in C57BL/Sv129 mice and assessed their relationship to the regulation of iron homeostasis in the duodenum and the liver, and their regulation by diet. We found an up to 14-fold variation in inter-individual expression of HFE mRNA in the duodenum. Mice with high duodenal HFE mRNA expression presented with significantly higher levels of TfR and DMT-1 mRNAs and an increased IRP-1 binding affinity as compared to mice with low HFE levels. Duodenal HFE expression was positively associated with serum iron and liver HFE levels. Dietary iron supplementation decreased HFE in the duodenum but not in the liver. This was paralleled by reduced amounts of DMT-1 and FP-1 in the duodenum while the expression of DMT-1, FP-1, and hepcidin in the liver were increased with dietary iron overload. Duodenal and liver HFE levels are regulated by divergent penetration of as yet unelucidated modifier genes and to a much lesser extent by dietary iron. These measures control duodenal iron transport and liver iron homeostasis by modulating HFE expression either directly or via stimulation of iron sensitive regulatory molecules, such as hepcidin, which then exert their effects on body iron homeostasis.
Ludwiczek
Susanne
S
Department of Internal Medicine, University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
Theurl
Igor
I
Artner-Dworzak
Erika
E
Chorney
Michael
M
Weiss
Guenter
G
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D004386:Duodenum / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D014644:Genetic Variation; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D007501:Iron / Q000097:blood / Q000378:metabolism*; D019266:Iron, Dietary / Q000494:pharmacology; D035925:Iron-Regulatory Proteins / Q000378:metabolism*; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis
D023181:Antimicrobial Cationic Peptides; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D019266:Iron, Dietary; D035925:Iron-Regulatory Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D007501:Iron