Physiologic systemic iron metabolism in mice deficient for duodenal Hfe.
Mutations in the Hfe gene result in hereditary hemochromatosis (HH), a disorder characterized by increased duodenal iron absorption and tissue iron overload. Identification of a direct interaction between Hfe and transferrin receptor 1 in duodenal cells led to the hypothesis that the lack of functional Hfe in the duodenum affects TfR1-mediated serosal uptake of iron and misprogramming of the iron absorptive cells. Contrasting this view, Hfe deficiency causes inappropriately low expression of the hepatic iron hormone hepcidin, which causes increased duodenal iron absorption. We specifically ablated Hfe expression in mouse enterocytes using Cre/LoxP technology. Mice with efficient deletion of Hfe in crypt- and villi-enterocytes maintain physiologic iron metabolism with wild-type unsaturated iron binding capacity, hepatic iron levels, and hepcidin mRNA expression. Furthermore, the expression of genes encoding the major intestinal iron transporters is unchanged in duodenal Hfe-deficient mice. Our data demonstrate that intestinal Hfe is dispensable for the physiologic control of systemic iron homeostasis under steady state conditions. These findings exclude a primary role for duodenal Hfe in the pathogenesis of HH and support the model according to which Hfe is required for appropriate expression of the "iron hormone" hepcidin which then controls intestinal iron absorption.
Vujic Spasic
Maja
M
Molecular Medicine Partnership Unit, University of Heidelberg, Germany.
Kiss
Judit
J
Herrmann
Thomas
T
Kessler
Regina
R
Stolte
Jens
J
Galy
Bruno
B
Rathkolb
Birgit
B
Wolf
Eckhard
E
Stremmel
Wolfgang
W
Hentze
Matthias W
MW
Muckenthaler
Martina U
MU
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D003573:Cytochrome b Group / Q000235:genetics / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism*; D020895:Enterocytes / Q000378:metabolism; D005260:Female; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D007408:Intestinal Absorption / Q000235:genetics; D007501:Iron / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000737:chemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D003573:Cytochrome b Group; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D007501:Iron; D008565:Membrane Proteins; D010088:Oxidoreductases; D012333:RNA, Messenger; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2; C579599:Hamp protein, mouse; C499535:Hfe protein, mouse; C498909:Cybrd1 protein, mouse