Suppression of SLC11A2 expression is essential to maintain duodenal integrity during dietary iron overload.
Iron is essential for the survival of mammals, but iron overload causes fibrosis and carcinogenesis. Reduced iron absorption and regulated release into circulation in duodenal mucosa constitute two major mechanisms of protection against dietary iron overload; however, their relative contribution remains elusive. To study the significance of the former process, we generated SLC11A2 transgenic mice (TGs) under the control of the chicken beta-actin promoter. TGs were viable and fertile, and displayed no overt abnormalities up to 20 months. No significant difference in iron concentration was observed in major solid organs between TGs and their wild-type littermates, suggesting that increased number of iron transporters does not lead to increased iron absorption. To test the sensitivity to iron overload, TGs and wild-type mice were fed with an iron-rich diet containing 2% ferric citrate. Iron supplementation caused suppression of endogenous duodenal SLC11A2 expression, down-regulation of duodenal ferroportin, and overexpression of hepatic hepcidin, precluding excessive iron uptake both in the TGs and wild-type mice. However, iron-treated TGs revealed increased mortality, resulting from oxidative mucosal damage leading to hemorrhagic erosion throughout the whole intestinal area. These findings suggest that reduced iron release from duodenal cells into circulation plays a role in mitigating excessive iron uptake from the diet and that finely regulated duodenal absorption is essential to protect intestinal mucosa from iron-induced oxidative damage.
Shirase
Tomoyuki
T
Department of Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Mori
Kiyoshi
K
Okazaki
Yasumasa
Y
Itoh
Ken
K
Yamamoto
Masayuki
M
Tabuchi
Mitsuaki
M
Kishi
Fumio
F
Jiang
Li
L
Akatsuka
Shinya
S
Nakao
Kazuwa
K
Toyokuni
Shinya
S
D000818:Animals; D019556:COS Cells; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004386:Duodenum / Q000378:metabolism*; D019190:Iron Overload / Q000378:metabolism*; D019266:Iron, Dietary / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress; D014018:Tissue Distribution; D000099236:Solute Carrier Family 11, Member 2
D027682:Cation Transport Proteins; D019266:Iron, Dietary; D000099236:Solute Carrier Family 11, Member 2