Inactivation of the hemochromatosis gene differentially regulates duodenal expression of iron-related mRNAs between mouse strains.
OBJECTIVE
Hfe knockout mice, like patients with hereditary hemochromatosis, have augmented duodenal iron absorption and increased iron deposition in hepatic parenchymal cells. The goals of the present study were to gain further insight into the control of iron absorption by comparing the transcript levels of iron-related genes in the duodenum of DBA/2 Hfe-/- mice, susceptible to iron loading, and wild-type controls, and to test whether variations in the duodenal expression of these messengers contribute to the DBA/2 and C57BL/6 strain differences in the severity of hepatic iron loading.


METHODS
Expression of the different transcripts was quantified by real-time polymerase chain reaction.


RESULTS
The 2 strains differ strikingly, not only in the severity of hepatic iron loading, but also in the duodenal expression of iron-related genes. In DBA/2 Hfe-/- mice, increased intestinal iron absorption results from the concomitant up-regulation of the Dcytb, DMT1, and FPN1 messengers. No increase in the expression of these messengers is seen in C57BL/6 Hfe-/- mice.


CONCLUSIONS
The up-regulation of these transcripts suggests that an inappropriate iron-deficiency signal is sensed by the duodenal enterocytes, leading to an enhanced ferric reductase activity and the increase of duodenal iron uptake and transfer to the circulation. The genes modifying the hemochromatosis phenotype probably act by modifying the expression of these 3 messengers.
Dupic
Françoise
F
Unité de Physiopathologie Cellulaire et Moléculaire, CNRS UPR 2163, CHU Purpan, Toulouse, France.
Fruchon
Séverine
S
Bensaid
Mounia
M
Borot
Nicolas
N
Radosavljevic
Mirjana
M
Loreal
Olivier
O
Brissot
Pierre
P
Gilfillan
Susan
S
Bahram
Siamak
S
Coppin
Hélène
H
Roth
Marie-Paule
MP
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics; D003573:Cytochrome b Group / Q000235:genetics; D004386:Duodenum / Q000502:physiology*; D015870:Gene Expression / Q000502:physiology; D006680:HLA Antigens / Q000235:genetics*; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D010088:Oxidoreductases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D013045:Species Specificity; D014168:Transferrin / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes; D015854:Up-Regulation / Q000502:physiology; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
D002352:Carrier Proteins; D027682:Cation Transport Proteins; D003573:Cytochrome b Group; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D007501:Iron; D033862:Iron-Binding Proteins; D008565:Membrane Proteins; D010088:Oxidoreductases; D012333:RNA, Messenger; D014168:Transferrin; D044763:Ubiquitin-Conjugating Enzymes; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2; C492164:HEPH protein, human; C117324:Heph protein, mouse; C499535:Hfe protein, mouse; C498909:Cybrd1 protein, mouse; C490789:Ube2d1 protein, mouse