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A nanoparticulate ferritin-core mimetic is well taken up by HuTu 80 duodenal cells and its absorption in mice is regulated by body iron.

Latunde-Dada GO, Pereira DI, Tempest B, Ilyas H, Flynn AC, Aslam MF, Simpson RJ, Powell JJ - J. Nutr. (2014)

Bottom Line: Silencing of the solute carrier family 11 (proton-coupled divalent metal ion transporter), member 2 (Slc11a2) gene (DMT1) significantly inhibited ferritin formation from FeSO4 (P = 0.005) but had no effect on uptake and utilization of nano Fe(III).Inhibiting DCYTB with an antibody also had no effect on uptake and utilization of nano Fe(III) but significantly inhibited ferritin formation from ferric nitrilotriacetate chelate (Fe-NTA) (P = 0.04).Similarly, cellular ferritin formation from nano Fe(III) was unaffected by the Fe(II) chelator ferrozine, which significantly inhibited uptake and utilization from FeSO4 (P = 0.009) and Fe-NTA (P = 0.005).

View Article: PubMed Central - PubMed

Affiliation: Diabetes and Nutritional Sciences Division, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom; and yemisi.latunde-dada@kcl.ac.uk.

ABSTRACT

Background: Iron (Fe) deficiency anemia remains the largest nutritional deficiency disorder worldwide. How the gut acquires iron from nano Fe(III), especially at the apical surface, is incompletely understood.

Objective: We developed a novel Fe supplement consisting of nanoparticulate tartrate-modified Fe(III) poly oxo-hydroxide [here termed nano Fe(III)], which mimics the Fe oxide core of ferritin and effectively treats iron deficiency anemia in rats.

Methods: We determined transfer to the systemic circulation of nano Fe(III) in iron-deficient and iron-sufficient outbread Swiss mouse strain (CD1) mice with use of (59)Fe-labeled material. Iron deficiency was induced before starting the Fe-supplementation period through reduction of Fe concentrations in the rodent diet. A control group of iron-sufficient mice were fed a diet with adequate Fe concentrations throughout the study. Furthermore, we conducted a hemoglobin repletion study in which iron-deficient CD1 mice were fed for 7 d a diet supplemented with ferrous sulfate (FeSO4) or nano Fe(III). Finally, we further probed the mechanism of cellular acquisition of nano Fe(III) by assessing ferritin formation, as a measure of Fe uptake and utilization, in HuTu 80 duodenal cancer cells with targeted inhibition of divalent metal transporter 1 (DMT1) and duodenal cytochrome b (DCYTB) before exposure to the supplemented iron sources. Differences in gene expression were assessed by quantitative polymerase chain reaction.

Results: Absorption (means ± SEMs) of nano Fe(III) was significantly increased in iron-deficient mice (58 ± 19%) compared to iron-sufficient mice (18 ± 17%) (P = 0.0001). Supplementation of the diet with nano Fe(III) or FeSO4 significantly increased hemoglobin concentrations in iron-deficient mice (170 ± 20 g/L, P = 0.01 and 180 ± 20 g/L, P = 0.002, respectively). Hepatic hepcidin mRNA expression reflected the nonheme-iron concentrations of the liver and was also comparable for both nano Fe(III)- and FeSO4-supplemented groups, as were iron concentrations in the spleen and duodenum. Silencing of the solute carrier family 11 (proton-coupled divalent metal ion transporter), member 2 (Slc11a2) gene (DMT1) significantly inhibited ferritin formation from FeSO4 (P = 0.005) but had no effect on uptake and utilization of nano Fe(III). Inhibiting DCYTB with an antibody also had no effect on uptake and utilization of nano Fe(III) but significantly inhibited ferritin formation from ferric nitrilotriacetate chelate (Fe-NTA) (P = 0.04). Similarly, cellular ferritin formation from nano Fe(III) was unaffected by the Fe(II) chelator ferrozine, which significantly inhibited uptake and utilization from FeSO4 (P = 0.009) and Fe-NTA (P = 0.005).

Conclusions: Our data strongly support direct nano Fe(III) uptake by enterocytes as an efficient mechanism of dietary iron acquisition, which may complement the known Fe(II)/DMT1 uptake pathway.

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Tissue Fe distribution in male CD1 mice after supplementation with nano Fe(III) and FeSO4. Nonheme-iron concentrations in the liver (A), spleen (B), and duodenum (C) of mice after 7-d feeding with test diets supplemented with nano Fe(III) or FeSO4. Concentrations in control mice maintained in the Fe-sufficient or the Fe-deficient diets throughout the study are also shown. Box and whisker plots show median, minimum, and maximum (n = 3 in the Fe-deficient group; n = 4 in each of the other groups). Labeled means without a common letter differ, P < 0.05 (1-factor ANOVA). FeSO4, ferrous sulfate.
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fig2: Tissue Fe distribution in male CD1 mice after supplementation with nano Fe(III) and FeSO4. Nonheme-iron concentrations in the liver (A), spleen (B), and duodenum (C) of mice after 7-d feeding with test diets supplemented with nano Fe(III) or FeSO4. Concentrations in control mice maintained in the Fe-sufficient or the Fe-deficient diets throughout the study are also shown. Box and whisker plots show median, minimum, and maximum (n = 3 in the Fe-deficient group; n = 4 in each of the other groups). Labeled means without a common letter differ, P < 0.05 (1-factor ANOVA). FeSO4, ferrous sulfate.

Mentions: Feeding the Fe-deficient diet for 4 wk reduced the nonheme-Fe concentration in the spleen (P = 0.003) and tended to reduce it in the liver (P = 0.07) of Fe-deficient mice compared with Fe-sufficient mice (Figure 2). The concentration in the duodenum did not differ among groups. Final hepatic and duodenal nonheme-Fe concentrations did not differ after 7 d of iron supplementation in the test diets with either nano Fe(III) or FeSO4 (Figure 2), and this was reflected by similar concentrations of Hamp1 mRNA in the 2 Fe-supplemented groups (Figure 1D). Nonheme-Fe concentrations in the spleen were still significantly lower than those in Fe-sufficient control mice for both nano Fe(III)- (P = 0.004) and FeSO4-supplemented (P = 0.008) groups and for the group maintained on the Fe-deficient diet throughout the study (P = 0.003) (Figure 2B).


A nanoparticulate ferritin-core mimetic is well taken up by HuTu 80 duodenal cells and its absorption in mice is regulated by body iron.

Latunde-Dada GO, Pereira DI, Tempest B, Ilyas H, Flynn AC, Aslam MF, Simpson RJ, Powell JJ - J. Nutr. (2014)

Tissue Fe distribution in male CD1 mice after supplementation with nano Fe(III) and FeSO4. Nonheme-iron concentrations in the liver (A), spleen (B), and duodenum (C) of mice after 7-d feeding with test diets supplemented with nano Fe(III) or FeSO4. Concentrations in control mice maintained in the Fe-sufficient or the Fe-deficient diets throughout the study are also shown. Box and whisker plots show median, minimum, and maximum (n = 3 in the Fe-deficient group; n = 4 in each of the other groups). Labeled means without a common letter differ, P < 0.05 (1-factor ANOVA). FeSO4, ferrous sulfate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230207&req=5

fig2: Tissue Fe distribution in male CD1 mice after supplementation with nano Fe(III) and FeSO4. Nonheme-iron concentrations in the liver (A), spleen (B), and duodenum (C) of mice after 7-d feeding with test diets supplemented with nano Fe(III) or FeSO4. Concentrations in control mice maintained in the Fe-sufficient or the Fe-deficient diets throughout the study are also shown. Box and whisker plots show median, minimum, and maximum (n = 3 in the Fe-deficient group; n = 4 in each of the other groups). Labeled means without a common letter differ, P < 0.05 (1-factor ANOVA). FeSO4, ferrous sulfate.
Mentions: Feeding the Fe-deficient diet for 4 wk reduced the nonheme-Fe concentration in the spleen (P = 0.003) and tended to reduce it in the liver (P = 0.07) of Fe-deficient mice compared with Fe-sufficient mice (Figure 2). The concentration in the duodenum did not differ among groups. Final hepatic and duodenal nonheme-Fe concentrations did not differ after 7 d of iron supplementation in the test diets with either nano Fe(III) or FeSO4 (Figure 2), and this was reflected by similar concentrations of Hamp1 mRNA in the 2 Fe-supplemented groups (Figure 1D). Nonheme-Fe concentrations in the spleen were still significantly lower than those in Fe-sufficient control mice for both nano Fe(III)- (P = 0.004) and FeSO4-supplemented (P = 0.008) groups and for the group maintained on the Fe-deficient diet throughout the study (P = 0.003) (Figure 2B).

Bottom Line: Silencing of the solute carrier family 11 (proton-coupled divalent metal ion transporter), member 2 (Slc11a2) gene (DMT1) significantly inhibited ferritin formation from FeSO4 (P = 0.005) but had no effect on uptake and utilization of nano Fe(III).Inhibiting DCYTB with an antibody also had no effect on uptake and utilization of nano Fe(III) but significantly inhibited ferritin formation from ferric nitrilotriacetate chelate (Fe-NTA) (P = 0.04).Similarly, cellular ferritin formation from nano Fe(III) was unaffected by the Fe(II) chelator ferrozine, which significantly inhibited uptake and utilization from FeSO4 (P = 0.009) and Fe-NTA (P = 0.005).

View Article: PubMed Central - PubMed

Affiliation: Diabetes and Nutritional Sciences Division, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom; and yemisi.latunde-dada@kcl.ac.uk.

ABSTRACT

Background: Iron (Fe) deficiency anemia remains the largest nutritional deficiency disorder worldwide. How the gut acquires iron from nano Fe(III), especially at the apical surface, is incompletely understood.

Objective: We developed a novel Fe supplement consisting of nanoparticulate tartrate-modified Fe(III) poly oxo-hydroxide [here termed nano Fe(III)], which mimics the Fe oxide core of ferritin and effectively treats iron deficiency anemia in rats.

Methods: We determined transfer to the systemic circulation of nano Fe(III) in iron-deficient and iron-sufficient outbread Swiss mouse strain (CD1) mice with use of (59)Fe-labeled material. Iron deficiency was induced before starting the Fe-supplementation period through reduction of Fe concentrations in the rodent diet. A control group of iron-sufficient mice were fed a diet with adequate Fe concentrations throughout the study. Furthermore, we conducted a hemoglobin repletion study in which iron-deficient CD1 mice were fed for 7 d a diet supplemented with ferrous sulfate (FeSO4) or nano Fe(III). Finally, we further probed the mechanism of cellular acquisition of nano Fe(III) by assessing ferritin formation, as a measure of Fe uptake and utilization, in HuTu 80 duodenal cancer cells with targeted inhibition of divalent metal transporter 1 (DMT1) and duodenal cytochrome b (DCYTB) before exposure to the supplemented iron sources. Differences in gene expression were assessed by quantitative polymerase chain reaction.

Results: Absorption (means ± SEMs) of nano Fe(III) was significantly increased in iron-deficient mice (58 ± 19%) compared to iron-sufficient mice (18 ± 17%) (P = 0.0001). Supplementation of the diet with nano Fe(III) or FeSO4 significantly increased hemoglobin concentrations in iron-deficient mice (170 ± 20 g/L, P = 0.01 and 180 ± 20 g/L, P = 0.002, respectively). Hepatic hepcidin mRNA expression reflected the nonheme-iron concentrations of the liver and was also comparable for both nano Fe(III)- and FeSO4-supplemented groups, as were iron concentrations in the spleen and duodenum. Silencing of the solute carrier family 11 (proton-coupled divalent metal ion transporter), member 2 (Slc11a2) gene (DMT1) significantly inhibited ferritin formation from FeSO4 (P = 0.005) but had no effect on uptake and utilization of nano Fe(III). Inhibiting DCYTB with an antibody also had no effect on uptake and utilization of nano Fe(III) but significantly inhibited ferritin formation from ferric nitrilotriacetate chelate (Fe-NTA) (P = 0.04). Similarly, cellular ferritin formation from nano Fe(III) was unaffected by the Fe(II) chelator ferrozine, which significantly inhibited uptake and utilization from FeSO4 (P = 0.009) and Fe-NTA (P = 0.005).

Conclusions: Our data strongly support direct nano Fe(III) uptake by enterocytes as an efficient mechanism of dietary iron acquisition, which may complement the known Fe(II)/DMT1 uptake pathway.

Show MeSH
Related in: MedlinePlus