Mammalian iron homeostasis is maintained at the level of absorption from the gut lumen. Iron absorption is known to respond to changes in iron stores, erythropoiesis, and hypoxia. Normal individuals absorb approximately 1 mg of dietary iron daily. In mild to moderate iron deficiency, this value increases to 3-5 mg/day. Estimates of iron absorption during severe iron deficiency or anemia range from 30-40 mg/day. Hypoxia response appears to be intermediate. We asked how mice respond to differences in dietary iron content. Groups of 8 mice were weaned onto diets containing 2, 35, 120, 350, and 2,000 mg/kg carbonyl iron for 4 wk, following which iron stores, hematological parameters, iron absorption, and expression of iron-related genes were compared. Mean hepatic iron content was 52.7 ± 3.7 μg/g (wet wt) in mice fed the 2 mg/kg diet and increased to 560 ± 23.7 μg/g in mice fed the 2,000 mg/kg diet. There was no difference in hepatic iron in mice fed 35-350 mg/kg diets and averaged 110 ± 3 μg/g. Mean spleen iron content was 132 ± 12.2 μg/g (wet wt) in mice maintained on 2 mg/kg and increased to 598 ± 49 μg/g in mice fed the 2,000 mg/kg diet. There was no difference in spleen iron in mice maintained on intermediate iron diets (mean 359 ± 10 μg/g). These data indicate that iron stores remained constant over a 10-fold range in dietary iron content and changed only at the extremes. Erythropoietic demand did not change over the entire range of dietary iron as no differences between groups were noted in hematocrit, hemoglobin, and MCV. Iron absorption was measured as percent of a measured dose of 59 Fe (5 μg total) remaining in the carcass (minus the GI tract) 24 h after administration by gavage. Absorption was inversely proportional to dietary iron content. Mean absorption was 86% ± 4, 42% ± 3, 26% ± 7, 19% ± 4 and 6% ± 1 on the 2, 35, 120, 350, and 2,000 mg/kg iron diets respectively. Real-time PCR was used to measure liver hepcidin mRNA. Hepcidin expression was 20-fold greater in mice on the 2,000 mg/kg diet than in mice on the 2 mg/kg diet (3,900 ± 1,021 vs 198 ± 47 copies/actin copy). Hepcidin expression did not differ in mice on intermediate diets (745 ± 147 copies). These data indicate that under conditions where iron stores are not changing and there is no evidence of altered erythropoiesis, iron absorption remained exquisitely sensitive to dietary iron content. This result suggests that over a broad range of dietary iron content, normal iron homeostasis is regulated by a factor(s) intrinsic to the enterocyte and not by “downstream” effects of iron stores and erythropoiesis.
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