title: A nanoparticulate ferritin-core mimetic is well taken up by HuTu 80 duodenal cells and its absorption in mice is regulated by body iron.
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.
authors.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.
authors.forename: Gladys O
authors.initials: GO
authors.lastname: Latunde-Dada
authors.affiliation: Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, United Kingdom.
authors.forename: Dora I A
authors.initials: DI
authors.lastname: Pereira
authors.affiliation: Diabetes and Nutritional Sciences Division, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom; and.
authors.forename: Bethan
authors.initials: B
authors.lastname: Tempest
authors.affiliation: Diabetes and Nutritional Sciences Division, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom; and.
authors.forename: Hibah
authors.initials: H
authors.lastname: Ilyas
authors.affiliation: Diabetes and Nutritional Sciences Division, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom; and.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Flynn
authors.affiliation: Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, United Kingdom.
authors.forename: Mohamad F
authors.initials: MF
authors.lastname: Aslam
authors.affiliation: Diabetes and Nutritional Sciences Division, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom; and.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Simpson
authors.affiliation: Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, United Kingdom.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Powell
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000188:drug therapy; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019587:Dietary Supplements; D004386:Duodenum / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D020895:Enterocytes / Q000378:metabolism; D005290:Ferric Compounds / Q000378:metabolism; D005293:Ferritins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005296:Ferrous Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D006454:Hemoglobins; D064451:Hepcidins / Q000235:genetics / Q000378:metabolism; D019266:Iron, Dietary / Q000008:administration & dosage / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D005290:Ferric Compounds; D005293:Ferritins; D005296:Ferrous Compounds; D006454:Hemoglobins; D064451:Hepcidins; D019266:Iron, Dietary; D009571:Nitrilotriacetic Acid; D014157:Transcription Factors; D000099236:Solute Carrier Family 11, Member 2; C110547:DMRT1 protein; C020748:ferrous sulfate; C020326:ferric nitrilotriacetate
keywords: cellular uptake; iron absorption; iron deficiency anemia; iron supplementation; tartrate-modified Fe(III) poly oxo-hydroxide