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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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Related in: MedlinePlus

In vivo bioavailability of nano Fe(III) and FeSO4 in male CD1 mice. Effect of iron status on the absorption of nano Fe(III) (A) or FeSO4 (B) in mice after oral gavage with 59Fe-labeled material. Box and whisker plots show median, minimum, and maximum (n = 6 per group). All values are expressed as percentage of dose (i.e., the radio iron that has left the stomach). *Different from the Fe-sufficient control within each body compartment, P < 0.05 (2-factor ANOVA). Hemoglobin concentrations (C) and Hamp1 mRNA expression (D) 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). CD1, outbread Swiss mouse strain; FeSO4, ferrous sulfate; Hamp1, hepcidin antimicrobial peptide 1.
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fig1: In vivo bioavailability of nano Fe(III) and FeSO4 in male CD1 mice. Effect of iron status on the absorption of nano Fe(III) (A) or FeSO4 (B) in mice after oral gavage with 59Fe-labeled material. Box and whisker plots show median, minimum, and maximum (n = 6 per group). All values are expressed as percentage of dose (i.e., the radio iron that has left the stomach). *Different from the Fe-sufficient control within each body compartment, P < 0.05 (2-factor ANOVA). Hemoglobin concentrations (C) and Hamp1 mRNA expression (D) 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). CD1, outbread Swiss mouse strain; FeSO4, ferrous sulfate; Hamp1, hepcidin antimicrobial peptide 1.

Mentions: First we were interested in assessing impact of systemic iron status on iron absorption of nano Fe(III). Hence, we compared iron absorption 4 h after gavage with a single dose of 59Fe- labeled FeSO4 or nano Fe(III) in iron-deficient and iron-sufficient mice (Figure 1A, B). As expected, iron absorption beyond gut uptake (i.e., systemic transfer) was significantly lower (P < 0.0001) in iron-sufficient mice than iron-deficient mice for FeSO4 (Figure 1B). There was also significantly higher systemic transfer of iron from nano Fe(III) in iron-deficient mice than iron-sufficient mice (P < 0.0001), but the iron retained in the duodenal tissue was not significantly different (Figure 1A). Iron retained in the jejunum, ileum, or colon would normally be considered as unabsorbed iron (i.e., in transit). Indeed, almost all of the unabsorbed iron from nano Fe(III) in iron-sufficient mice could be accounted for in the ileal and colonic samples (Figure 1A). Over the 4-h period, 49 ± 17% of the gavaged iron was transferred systemically for nano Fe(III) vs. 70 ± 11% for ferrous sulfate (P = 0.03), although absolute comparisons in absorption are not easy because of likely differences in kinetics of uptake as observed in humans (28).


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)

In vivo bioavailability of nano Fe(III) and FeSO4 in male CD1 mice. Effect of iron status on the absorption of nano Fe(III) (A) or FeSO4 (B) in mice after oral gavage with 59Fe-labeled material. Box and whisker plots show median, minimum, and maximum (n = 6 per group). All values are expressed as percentage of dose (i.e., the radio iron that has left the stomach). *Different from the Fe-sufficient control within each body compartment, P < 0.05 (2-factor ANOVA). Hemoglobin concentrations (C) and Hamp1 mRNA expression (D) 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). CD1, outbread Swiss mouse strain; FeSO4, ferrous sulfate; Hamp1, hepcidin antimicrobial peptide 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: In vivo bioavailability of nano Fe(III) and FeSO4 in male CD1 mice. Effect of iron status on the absorption of nano Fe(III) (A) or FeSO4 (B) in mice after oral gavage with 59Fe-labeled material. Box and whisker plots show median, minimum, and maximum (n = 6 per group). All values are expressed as percentage of dose (i.e., the radio iron that has left the stomach). *Different from the Fe-sufficient control within each body compartment, P < 0.05 (2-factor ANOVA). Hemoglobin concentrations (C) and Hamp1 mRNA expression (D) 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). CD1, outbread Swiss mouse strain; FeSO4, ferrous sulfate; Hamp1, hepcidin antimicrobial peptide 1.
Mentions: First we were interested in assessing impact of systemic iron status on iron absorption of nano Fe(III). Hence, we compared iron absorption 4 h after gavage with a single dose of 59Fe- labeled FeSO4 or nano Fe(III) in iron-deficient and iron-sufficient mice (Figure 1A, B). As expected, iron absorption beyond gut uptake (i.e., systemic transfer) was significantly lower (P < 0.0001) in iron-sufficient mice than iron-deficient mice for FeSO4 (Figure 1B). There was also significantly higher systemic transfer of iron from nano Fe(III) in iron-deficient mice than iron-sufficient mice (P < 0.0001), but the iron retained in the duodenal tissue was not significantly different (Figure 1A). Iron retained in the jejunum, ileum, or colon would normally be considered as unabsorbed iron (i.e., in transit). Indeed, almost all of the unabsorbed iron from nano Fe(III) in iron-sufficient mice could be accounted for in the ileal and colonic samples (Figure 1A). Over the 4-h period, 49 ± 17% of the gavaged iron was transferred systemically for nano Fe(III) vs. 70 ± 11% for ferrous sulfate (P = 0.03), although absolute comparisons in absorption are not easy because of likely differences in kinetics of uptake as observed in humans (28).

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