Intestinal iron uptake determined by divalent metal transporter is enhanced in HFE-deficient mice with hemochromatosis.
OBJECTIVE
Overexpression of duodenal divalent metal transporter (DMT1) messenger RNA occurs in hemochromatosis and HFE-knockout mice, suggesting that DMT1 mediates enhanced absorption of iron; however, increased expression of functional DMT1 protein has yet to be substantiated. We examined the role of DMT1 and the mucosal iron uptake defect in HFE-knockout mice.


METHODS
Unidirectional iron uptake of 59Fe by small intestinal mucosa in vitro was compared between matched pairs of HFE-knockout and wild-type mice. DMT1-specific antibodies were used to block iron transport and to quantify duodenal protein expression.


RESULTS
Ferrous iron uptake at 3.5-450 micromol/L was greatly enhanced in HFE-knockouts compared with wild-type, the apparent V(max) for Fe2+ transport being doubled (P < 0.01). Supplied as Fe3+, uptake was only enhanced in HFE-knockouts at < or =18 micromol/L, when the iron was almost completely converted to Fe2+ by mucosal ferrireductases. DMT1 antibody reduced the apparent Vmax for mucosal Fe2+ transport in HFE-knockouts to below wild-type control values (P < 0.02); immunoreactive mucosal DMT1 protein was increased nearly 2-fold in HFE-knockouts (P < 0.01).


CONCLUSIONS
Disruption of the HFE gene up-regulates functional DMT1 transporters and enhances uptake of ferrous iron by this mechanism; DMT1 also mediates increased uptake after reduction of ferric iron presented at physiological concentrations.
Griffiths
W J
WJ
University of Cambridge Department of Medicine, Addenbrooke's Hospital, Cambridge, England.
Sly
W S
WS
Cox
T M
TM
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D027682:Cation Transport Proteins; D005260:Female; D006680:HLA Antigens / Q000235:genetics*; D006432:Hemochromatosis / Q000378:metabolism* / Q000628:therapy; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D000099236:Solute Carrier Family 11, Member 2
D002352:Carrier Proteins; D027682:Cation Transport Proteins; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D007501:Iron; D033862:Iron-Binding Proteins; D008565:Membrane Proteins; D000099236:Solute Carrier Family 11, Member 2; C499535:Hfe protein, mouse