New perspectives on the regulation of iron absorption via cellular zinc concentrations in humans

References

• Abboud, S. and Haile, D. J. (2000). A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J. Biol. Chem. 275(26):19906–19912.
   PubMed Web of Science ®Google Scholar
• Alarcon, K., Kolsteren, W. P., Prada, M. A., Chian, M. A. et al. (2004). Effects of separate delivery of zinc or zinc and vitamin A on hemoglobin response, growth, and diarrhea in young Peruvian children receiving iron therapy for anemia. Am. J. Clin. Nutr. 80:1276–1282.
   PubMed Web of Science ®Google Scholar
• Allen, H. L., Rosado, L. J., Casterline, E. J., Lo´pez, P., Muñoz, E., Garcia, P. O. and Martinez, H. (2000). Lack of hemoglobin response to iron supplementation in anemic Mexican preschoolers with multiple micronutrient deficiencies. Am. J. Clin. Nutr. 71:1485–1494.
   PubMed Web of Science ®Google Scholar
• Andrews, K. (2008). Regulation and function of Zip4, the acrodermatitis enteropathica gene. Biochem. Soc. Trans. 6(36):1242–1246.
   Web of Science ®Google Scholar
• Aydemir, T. B., Chang, S. M., Guthrie, G. J., Maki, A. B., Ryu, M. S., Karabiyik, A. and Cousins, R. J. (2012). Zinc transporter ZIP14 functions in hepatic Zinc, Iron and Glucose homeostasis during the innate immune response (Endotoxemia). Plos One. 7(10).
   PubMed Web of Science ®Google Scholar
• Aydemir, F., Jenkitkasemwong, S., Gulec, S. and Knutson, M. D. (2009). Iron loading increases ferroportin heterogeneous nuclear RNA and mRNA levels in murine J774 macrophages. J. Nutr. 139(3):434–438.
   PubMed Web of Science ®Google Scholar
• Balesaria, S., Ramesh, B., McArdle, H., Bayele, H. K. and Srai, S. K. S. (2010). Divalent metal-dependent regulation of hepcidin expression by MTF-1. Febs. Lett. 584(4):719–725.
   PubMed Web of Science ®Google Scholar
• Bannon, D. I., Bressler, J. P., Abounader, R. and Lees, P. S. (2003). Effect of DMT1 knockdown on iron, cadmium, and lead uptake in Caco-2 cells. Toxicol. Sci. 72:402–402.
   Web of Science ®Google Scholar
• Bao, B., Prasad, A. S., Beck, F. W. and Sarkar, F. H. (2007). Zinc up-regulates NF-kappaB activation via phosphorylation of IkappaB in HUT-78 (Th0) cells. FEBS Lett. 581(23):4507–4511.
   PubMed Web of Science ®Google Scholar
• Beaton, G. H. and McCabe, G. P. (1999). Efficacy of intermittent iron supplements in the control of iron deficiency anaemia in developing countries: an analysis of experience. The Micronutrient Initiative, Toronto.
   Google Scholar
• Begum, N. A., Kobayashi, M., Moriwaki, Y., Matsumoto, M., Toyoshima, K. and Seya, T. (2002). Mycobacterium bovis BCG cell wall and lipopoly-saccharide induce a novel gene, BIGM103, encoding a 7-TM protein. Identification of a new protein family having Zn-transporter and Zn-met- alloprotease signatures. Genomics. 80:630–645.
   PubMed Web of Science ®Google Scholar
• Bishop, G. M., Shreiber, I. A., Dringen, R. and Robinson, S. R. (2010). Synergistic accumulation of iron and zinc by cultured astrocytes. J. Neural. Transm. 117(7):809–817.
   PubMed Web of Science ®Google Scholar
• Brown, N. M., Anderson, S. A., Steffen, D. W., Carpenter, T. B., Kennedy, M. C., Walden, W. E. and Eisenstein, R. S. (1998). Novel role of phosphorylation in Fe-S cluster stability revealed by phosphomimetic mutations at Ser 138 of IRP 1. Proc. Natl. Acad. Sci. 95:15235–15240.
   PubMed Web of Science ®Google Scholar
• Butcher, H., Kennette, W. A., Collins, O., Zalups, R. K. and Koropatnick, J. (2004). Metallothionein mediates the level and activity of nuclear factor kappa B in murine fibroblasts. J. Pharmacol. Exp. Ther. 2589–2598.
   Web of Science ®Google Scholar
• Butt, J., Armstrong, F. A., Breton, J., George, S. J., Thomson, A. J. and Hatchikian, E. C. (1991). Investigation of metal ion uptake reactivities of 3 iron 4 sulfur clusters in proteins voltammetry of co adsorbed ferredoxin aminocyclitol films at graphite electrodes and spectroscopic identification of transformed clusters. J. Am. Chem. Soc. 113(17):6663–6670.
   Web of Science ®Google Scholar
• Chang, S., El Arifeen, S., Bari, S., Wahed, M. A., Rahman, K. M., Rahman, M. T., Mahmud, A. B., Begum, N., Zaman, K., Baqui, A. H. and Black, R. E. (2010). Supplementing iron and zinc: Double blind, randomized evaluation of separate or combined delivery. Eur. J. Clin. Nutr. 64:153–160.
   PubMed Web of Science ®Google Scholar
• Chiabrando, D., Fiorito, V., Marro, S., Silengo, L., Altruda, F. and Tolosano, E. (2013). Cell-specific regulation of Ferroportin transcription following experimentally-induced acute anemia in mice. Blood Cells Mol. Dis. 50(1):25–30.
   PubMed Web of Science ®Google Scholar
• Chung, B., Chaston, T., Marks, J., et al. (2009). Hepcidin decreases iron transporter expression in vivo in mouse duodenum and spleen and in vitro in THP-1 macrophages and intestinal Caco-2 cells. J. Nutr. Rev. 139:1457–1462.
   Web of Science ®Google Scholar
• Cousins, R. J. (2010). Gastrointestinal factors influencing zinc absorption and homeostasis. Int. J. Vitam. Nutr. Res. 80(4–5):243–248.
   PubMed Web of Science ®Google Scholar
• Cousins, R. J. and McMahon, R. J. (2000). Integrative aspects of zinc transporters. J. Nutr. 130(5):1384–1387.
   Web of Science ®Google Scholar
• Dada, G. L., Van der Westhuizen, J., Vulpe, Anderson, J., Simpson, R. and McKie, A. (2008). Molecular and functional roles of duodenal cytochrome B (Dcytb) in iron metabolism. Blood Cells Mol. Dis. 29:356–360.
   Web of Science ®Google Scholar
• Dufner-Beattie, J., Kuo, Y. M., Gitschier, J. and Andrews, G. K. (2004). The adaptive response to dietary zinc in mice involves the differential cellular localization and zinc regulation of the zinc transporters ZIP4 and ZIP5. J. Biol. Chem. 279:49082.
   PubMed Web of Science ®Google Scholar
• Deng, Z., Dailley, L. A., Soukup, J., Stonehuerner, J., Richards, J. D., Callaghan, K. D., Yang, F. and Ghio, A. J. (2009). Zinc transport by respiratory epithelial cells and interaction with iron homeostasis. Biometals. 22:803–815.
   PubMed Web of Science ®Google Scholar
• De Benoist, B., Darnton-Hill, I., Davidsson, L., Fontaine, O. and Hotz, C. (2007). Conclusions of the joint WHO/UNICEF/IAEA/IZiNCG interagency meeting on zinc status indicators. Food. Nutr. Bull. 28:S480–S484.
   PubMed Web of Science ®Google Scholar
• Donovan, A., Lima, C. A., Pinkus, J. L., Pinkus, G. S., Zon, L. I., Robine, S. and Andrews, N. C. (2005). The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metabolism. 1(3):191–200.
   PubMed Web of Science ®Google Scholar
• Ece, A., Uyamik, B. S., Iscan, A., Ertan, P. and Yigitolu, M. R. (1997). Increased serum copper and decreased serum zinc levels in children with iron deficiency anemia. Biol. Trace Elem. Res. 59:31–39.
   PubMed Web of Science ®Google Scholar
• Eide, D. J. (2004). The SLC39 family of metal ion transporters. Pflugers Arch. –Eur. J. Phys. 447(5):796–800.
   PubMed Web of Science ®Google Scholar
• Eide, D. J. (2006). Zinc transporters and the cellular trafficking of zinc. Bioch. Et Biophys. Acta Mol Cell Res. 1763(7):711–722.
   PubMed Web of Science ®Google Scholar
• Eisenstein, R. S. and Blemings, K. P. (1998). Iron regulatory proteins, iron responsive elements and iron homeostasis. J. Nutr. 128(12):2295–2298.
   PubMed Web of Science ®Google Scholar
• Esamai, F., Liechty, E., Ikemeri, J. et al. (2014). Zinc absorption from micronutrient powder is low but is not affected by iron in Kenyan infants. Nutrients. 6(12):5636–5651.
   PubMed Web of Science ®Google Scholar
• Espinoza, A., Le Blanc, S., Olivares, M., Pizarro, F., Ruz, M. and Arredondo, M. (2012). Iron, copper, and zinc transport: Inhibition of divalent metal transporter 1 (DMT1) and human copper transporter 1 (hCTR1) by shRNA. Biol. Trace Elem. Res. 146(2):281–286.
   PubMed Web of Science ®Google Scholar
• Fernandes, A. P. G., Phung, Y., De Domenico, I., Kaplan, J., Ganz, T. and Nemeth, E. (2009). The molecular basis of hepcidin-resistant hereditary hemochromatosis. Blood. (114):437–443.
   PubMed Web of Science ®Google Scholar
• Fischer-Walker, C., Kordas, K., Stoltzfus, R. J. and Black, R. E. (2005). Interactive effects of iron and zinc on biochemical and functional outcomes in supplementation trials. Am. J. Clin. Nutr. 82:5–12.
   PubMed Web of Science ®Google Scholar
• Folgueras, A., Martin, de L. F., Pendas, A. M., Garabaya, C., Rodriguez, F., Astudillo, A., Bernal, T., Cabanillas, R., Lopez-Otin, C., et al. (2008). The membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood. 112(112):2539–2545.
   PubMed Web of Science ®Google Scholar
• Frazer, D. M., Wilkins, S. J., Becker, E. M., Murphy, T. L., Vulpe, C. D., McKie, A. T. and Anderson, G. J. (2003). A rapid decrease in the expression of DMT1 and Dcytb but not Ireg1 or hephaestin explains the mucosal block phenomenon of iron absorption. Gut. 52:340–346.
   PubMed Web of Science ®Google Scholar
• Fuqua, B. K., Vulpe, C. D. and Anderson, G. J. (2012). Intestinal iron absorption. J. Trace Elem. Med. Biol. 26(2–3):115–119.
   PubMed Web of Science ®Google Scholar
• Galvez-Peralta, M., He, L., Jorge-Nebert, L. F., Wang, B., Miller, M. L., Eppert, B. L., Afton, S. and Nebert, D. W. (2012). ZIP8 zinc transporter: Indispensable role for both multiple-organ organogenesis and hematopoiesis in utero. Plos One. 7(5).
   PubMed Web of Science ®Google Scholar
• Ganz, T. (2011). Hepcidin and iron regulation, 10 years later. Blood. 117:4425–4433.
   PubMed Web of Science ®Google Scholar
• Ganz, T. and Nemeth, E. (2006). Regulation of iron acquisition and iron distribution in mammals. Biochim. Biophys. Acta. 1763:690–699.
   PubMed Web of Science ®Google Scholar
• Gao, J., Zhao, N., Knutson, M. D. and Enns, C. A. (2008). The hereditary hemochromatosis protein, HFE, inhibits iron uptake via down-regulation of Zip14 in HepG2 cells. J. Biol. Chem. 283(31):21462–21468.
   PubMed Web of Science ®Google Scholar
• Garrick, M. D., Singleton, S. T., Vargas, F., Kuo, H. C., Zhao, L., Knopfel, M., Davidson, T., Costa, M., Paradkar, P., Roth, J. A. and Garrick, L. M. (2006). DMTI: Which metals does it transport? Biol. Res. 39(1):79–85.
   PubMed Web of Science ®Google Scholar
• Gebremedhin, S., Enquselassie, F. and Umet, a. M. (2014). Prevalence and correlates of maternal anemia in rural Sidama, southern Ethiopia. Afr. J. Reprod. Health. 18(1):44–53.
   PubMed Web of Science ®Google Scholar
• Gleeson, F., Ryan, E., Barrett, S., Russell, J., Kelleher, B. and Crowe, J. (2005). Duodenal Dcytb and hephaestin mRNA expression are not significantly modulated by variations in body iron homeostasis. Blood Cells, Mol. Dis. 35:303–308.
   PubMed Web of Science ®Google Scholar
• Gibson, R. S., Abebe, Y., Stabler, S., Allen, H. R., Westcott, J. E., Stoecker, J. B., Krebs, F. N. and Hambidge, M. K. (2008). Zinc, gravida, infection and iron, but not vit.B12 or folate status predict hemoglobin during pregnancy in Southern Ethiopia. J. Nutr. 138:581–586.
   PubMed Web of Science ®Google Scholar
• Gifford, C. A., Holland, B. P., Mills, R. L., Maxwell, C. L. and Farney, J. K. (2012). Growth and development symposium: Impacts of inflammation on cattle growth and carcass merit. J. Anim. Sci. 90:1438–1451.
   PubMed Web of Science ®Google Scholar
• Girijashanker, K., He, L., Soleimani, M., Reed, J. M., Li, H., et al. (2008). Slc39a14 gene encodes ZIP14, a metal/bicarbonate symporter: similarities to the ZIP8 transporter. Mol. Pharmacol. 73(5):1413–1423.
   PubMed Web of Science ®Google Scholar
• Gonçalves, A. S., Muzeau, F., Blaybel, R., Hetet, G., Driss, F., Delaby, C., Canonne-Hergaux, F. and Beaumont, C. (2006). Wild-type and mutant ferroportins do not form oligomers in transfected cells. Biochem. J. 396:265–275.
   PubMed Web of Science ®Google Scholar
• Gunshin, H., Fujiwara, Y., Custodio, A. O., Direnzo, C., Robine, S. and Andrews, N. C. (2005a). Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J. Clin. Invest. 115:1258–1266.
   PubMed Web of Science ®Google Scholar
• Gunshin, H., Starr, C. N., Direnzo, C., Fleming, M. D., Jin, J., Greer, E. L., Sellers, V. M., Galica, S. M. and Andrews, N. C. (2005b). Cybrd1 (duodenal cytochrome b) is not necessary for dietary iron absorption in mice. Blood. 106:2879–2883.
   PubMed Web of Science ®Google Scholar
• Haase, V. H. (2010). Hypoxic regulation of erythropoiesis and iron metabolism. Am. J. Physiol. Renal Physiol. 299(1):F1–F13.
   PubMed Web of Science ®Google Scholar
• Hambidge, K. M., Miller, L. V., Westcott, J. E., Sheng, X. and Krebs, N. F. (2010). Zinc bioavailability and homeostasis. Am. J. Clin. Nutr. 91:S1478–S1483.
   PubMed Web of Science ®Google Scholar
• Harrison, P. M. (1996). The ferritins: Molecular properties, iron storage functions and cellular regulation. Biochim. Biophys. Acta. 1275:161–203.
   PubMed Web of Science ®Google Scholar
• Harvey, J. L., Dainty, R. J., Hollands, J. W., Bull, J. V., Hoogewerff, A. J., Foxal, J. R., McAnena, L., Strain, J. J. and Fairweather-Tait, J. S. (2007). Effect of high-dose iron supplements on fractional zinc absorption and status in pregnant women. Am. J. Clin. Nutr. 85:131–136.
   PubMed Web of Science ®Google Scholar
• Hininger-Favier, I., Andriollo-Sanchez, M., Arnaud, J., et al. (2007). Age- and sex-dependent effects of long-term zinc supplementation on essential trace element status and lipid metabolism in European subjects: The Zenith Study. Br. J. Nutr. 97:569–578.
   PubMed Web of Science ®Google Scholar
• Ho, E. and Ames, B. N. (2002). Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFkappa B, and AP1 DNA binding and affects DNA repair in a rat glioma cell line. Proc. Natl. Acad. Sci. USA. 99:16770–16775.
   PubMed Web of Science ®Google Scholar
• Hossain, M. B., Kelleher, S. L. and Loennerdal, B. (2011). Maternal iron and zinc supplementation during pregnancy affects body weight and iron status in rat pups at weaning. J. Nutr. 141(5):798–804.
   PubMed Web of Science ®Google Scholar
• Illing, A. C., Shawki, A., Cunningham, C. L. and Mackenzie, B. (2012). Substrate profile and metal-ion selectivity of human divalent metal-ion transporter-1. J. Biol. Chem. 287(36):30485–30496.
   PubMed Web of Science ®Google Scholar
• Iyengar, V., Pullakhandam, R. and Nair, K. M. (2009). Iron–zinc interaction during uptake in human intestinal Caco-2 cell line: Kinetic analyses and possible mechanism. Ind. J. Biochem. Biophys. 46:299–306.
   PubMed Web of Science ®Google Scholar
• Iyengar, V., Pullakhandam, R. and Nair, K. M. (2012). Coordinate expression and localization of iron and zinc transporters explain iron-zinc interactions during uptake in Caco-2 cells: Implications for iron uptake at the enterocyte. J. Nutr. Biochem. 23(9):1146–1154.
   PubMed Web of Science ®Google Scholar
• Jenkitkasemwong, S., Wang, C. Y., Mackenzie, B. and Knutson, M. D. (2012). Physiologic implications of metal-ion transport by ZIP14 and ZIP8. Biometals. 25:643–655.
   PubMed Web of Science ®Google Scholar
• Jou, M. Y., Philipps, A. F., Kelleher, S. L. and Lonnerdal, B. (2010). Effects of zinc exposure on zinc transporter expression in human intestinal cells of varying maturity. J. Pediatr. Gastroenterol. Nutr. 50(6):587–595.
   PubMed Web of Science ®Google Scholar
• Kaluza, J., Madej, D., Rusaczonek, A. et al. (2014). Plasma zinc, vitamin B-12 and alpha-tocopherol are positively and plasma gamma-tocopherol is negatively associated with Hb concentration in early pregnancy in north-west Bangladesh. Eur. J. Nutr. 53(4):1083–1092.
   PubMed Web of Science ®Google Scholar
• Kelleher, S. L. and Lonnerdal, B. (2006). Zinc supplementation reduces iron absorption through age-dependent changes in small intestine iron transporter expression in suckling rat pups. J. Nutr. 136:1185–1191.
   PubMed Web of Science ®Google Scholar
• Kim, B. E., Wang, F. D., Dufner-Beattie, J., Andrews, G. K., Eide, D. J. and Petris, M. J. (2004). Zn2+-stimulated endocytosis of the mZIP4 zinc transporter regulates its location at the plasma membrane. J. Biol. Chem. 279:4523–4530.
   PubMed Web of Science ®Google Scholar
• King, J. C. (2010). Does zinc absorption reflect zinc status? Int. J. Vitam. Nutr. Res. 80(4–5):300–306.
   PubMed Web of Science ®Google Scholar
• King, J. C. and Cousins, R. J. (2006). Zinc. Modern Nutrition in Health and Disease 10th. Lippincott Williams & Wilkins, Baltimore.
   Google Scholar
• Knutson, M. D. (2009). Into the matrix: Regulation of the iron regulatory hormone hepcidin by matriptase-2. Nutr. Rev. 67(5):284–288.
   PubMed Web of Science ®Google Scholar
• Knutson, M. D., Vafa, M. R., Haile, D. J. and Wessling-Resnick, M. (2003). Iron loading and erythrophagocytosis increase ferroportin 1 (FPN1) expression in J774 macrophages. Blood. 102:4191–4197.
   PubMed Web of Science ®Google Scholar
• Kolsteren, P., Rahman, S. R., Hilderbrand, K. and Diniz, A. (1999). Treatment for iron deficiency anemia with a combined supplementation of iron, vitamin A and zinc in women of Dinajpur, Bangladesh. Eur. J. Clin. Nutr. 53:102–107.
   PubMed Web of Science ®Google Scholar
• Kordas, K. and Stolzfus, J. R. (2004). Evidence of iron and zinc interplay at the enterocyte and neural tissues. J. Nutr. 134:1295–1298.
   PubMed Web of Science ®Google Scholar
• Lagnel, B., Karim, Z., Letteron, P., Bekri, S., Bado, A. and Beaumont, C. (2011). Intestinal DMT1 cotransporter is down-regulated by hepcidin via proteasome internalization and degradation. Gastroenterology. 140(4):1261–1265.
   PubMed Web of Science ®Google Scholar
• Langmade, S. J., Ravindra, R., Daniels, P. J. and Andrews, G. K. (2010). The transcription factor MTF-1 mediates metal regulation of the mouse ZnT1 gene. J. Biol. Chem. 275:34803.
   Web of Science ®Google Scholar
• Lasocki, S., Millot, S., Andrieu, V., et al. (2008). Phlebotomies or erythropoietin injections allow mobilization of iron stores in a mouse model mimicking intensive care anemia. Crit. Care Med. 36:2388–2394.
   PubMed Web of Science ®Google Scholar
• Lee, P. L. and Beutler, E. (2009). Regulation of hepcidin and iron-overload disease. Ann. Rev. Pathol. Mech. Dis. 489–515.
   PubMed Web of Science ®Google Scholar
• Leong, W. I., Bowlus, L. C., Tallkvist, J. and Lonnerdal, B. (2003). Iron supplementation during infancy—Effects on expression of iron transporters, iron absorption and iron utilization in rat pups. Am. J. Clin. Nutr. 78:1203–1211.
   PubMed Web of Science ®Google Scholar
• Leong, W. and Lonnerdal, B. (2004). Hepcidin, the recently identified peptide that appears to regulate iron absorption. Br. J. Nutr. 134:1–4.
   Google Scholar
• Liang, G., Louis, A., Lichten,  , […] and Cousins, R. J. (2010). STAT5-glucocorticoid receptor interaction and MTF-1 regulate the expression of ZnT2 (Slc30a2) in pancreatic acinar cells. PNAS. 107(7):2818–2823.
   PubMed Web of Science ®Google Scholar
• Lichten, L. A. and Cousins, R. J. (2009). Mammalian zinc transporters: Nutritional and physiologic regulation. Ann. Rev. Nutr. 153–176.
   PubMed Web of Science ®Google Scholar
• Liu, S., Chen Z. J. (2011). Expanding role of ubiquitination in NF-κB signaling. Cell Res. 21(1):6–21.
   PubMed Web of Science ®Google Scholar
• Liu, X. B., Yang, F. and Haile, D. J. (2005). Functional consequences of ferroportin 1 mutations. Blood Cells Mol. Dis. 35:33–46.
   PubMed Web of Science ®Google Scholar
• Liuzzi, J. P., Aydemir, F., Nam, H., Knutson, M. D. and Cousins, R. J. (2006). Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc. Natl. Acad. Sci. 103:13612–13617.
   PubMed Web of Science ®Google Scholar
• Liuzzi, J. P., Bobo J. A., Cui, L., McMahon. R. J. and Cousins, R. J. (2003). Zinc transporters 1, 2 and 4 are differentially expressed and localized in rats during pregnancy and lactation. J Nutr. 133:342–351.
   PubMed Web of Science ®Google Scholar
• Liuzzi, J. P., Bobo, J. A., Lichten, L. A., Samuelson, D. A. and Cousins, R. J. (2004). Responsive transporter genes within the murine intestinal-pancreatic axis form a basis of zinc homeostasis. Proc. Natl. Acad. Sci. USA. 101:14355.
   PubMed Web of Science ®Google Scholar
• Liuzzi, J. P., Lichten, L. A., Rivera, S., Blanchard, R. K., Aydemir, T. B., Knutson, M. D., Ganz, T. and Cousins, R. J. (2005). Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response. Proc. Natl. Acad. Sci. USA. 102(19):6843–6848.
   PubMed Web of Science ®Google Scholar
• Lonnerdal, B. (2000). Dietary factors influencing zinc absorption. J. Nutr. 130:S1378–S1383.
   PubMed Web of Science ®Google Scholar
• Lopez de Romana, D., Lonnerdal, B. and Brown, H. K. (2003). Absorption of zinc from wheat products fortified with iron and either zinc sulfate or zinc oxide. Am. J. Clin. Nutr. 78:279–283.
   PubMed Web of Science ®Google Scholar
• Lopez deRomana, D., Lonnerdal, B. and Brown, H. K. (2005). Longitudinal measurements of zinc absorption in Peruvian children consuming wheat products fortified with iron only or iron an 1 of 2 amounts of zinc. Am. J. Clin. Nutr. 81:637–647.
   PubMed Web of Science ®Google Scholar
• Lymboussaki, A., Pignatti, E., Montosi, G., Garuti, G., Haile, D. J. and Pietrangelo, A. (2003). The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression. J. Hepatol. 39:710–715.
   PubMed Web of Science ®Google Scholar
• Ma, A. G., Chen, X. C., Xu, R. X., Zheng, M. C., Wang, Y. and Li, J. S. (2004). Comparison of serum levels of iron, zinc and copper in anaemic and non-anaemic pregnant women in China. Asia Pac. J. Clin. Nutr. 13:348–352.
   PubMed Web of Science ®Google Scholar
• Mello-Neto , Rondó, P. H., Oshiiwa, M., Morgano, M. A. et al. (2003). Duodenal cytochrome and hephaestin expression in patients with iron deficiency and hemochromatosis. Gastroenterology. 125(3):746–754.
   PubMed Web of Science ®Google Scholar
• Mackenzie, B., Takanaga, H., Hubert, N., Rolfs, A. and Hediger, M. A. (2007). Functional properties of multiple isoforms of human divalent metal-ion transporter 1 (DMT1). Biochem. J. 403:59–69.
   PubMed Web of Science ®Google Scholar
• Mastrogiannaki, M., Matak, P., Keith, B., Simon, M. C., Vaulont, S. and Peyssonnaux, C. (2009). HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J. Clin. Invest. 119:1159–1166.
   PubMed Web of Science ®Google Scholar
• McArdle, H. J., Lang, C., Hayes, H. and Gambling, L. (2011). Role of the placenta in regulation of fetal iron status. Nutr. Rev. 69(1):S17–S22.
   PubMed Web of Science ®Google Scholar
• McKie, A. T. (2008). The role of Dcytb in iron metabolism: an update. Biochem. Soc. Trans. 36:1239–1241.
   PubMed Web of Science ®Google Scholar
• McKie, A. T., Marciani, P., Rolfs, A., Brennan, K., Wehr, K., Barrow, D., Miret, S., Bomford, A., Peters, T. J., Farzaneh, F., Hediger, M. A., Hentze, M. W. and Simpson, R. J. (2000). A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol. Cell. 5(2):299–309.
   PubMed Web of Science ®Google Scholar
• McMahon, R. J. and Cousins, R. J. (1998). Regulation of the zinc transporter ZnT-1 by dietary zinc. Proc. Natl. Acad. Sci. 95(9):4841–4846.
   PubMed Web of Science ®Google Scholar
• Meerarani, P., Reiterer, G., Toborek, M. and Hennig, B. (2003). Zinc modulates PPAR signaling and activation of porcine endothelial cells. J. Nutr. 133:3058–3064.
   PubMed Web of Science ®Google Scholar
• Mena, N. P., Esparza, A. and Tapia, V. (2008). Hepcidin inhibits apical iron uptake in intestinal cells. Am. J. Physiol. Gastrointest. Liver Physiol. 294:G192–G198.
   PubMed Web of Science ®Google Scholar
• Mocchegiani, E., Costarelli, L., Giacconi, R., Piacenza, F., Basso, A. and Malavolta, M. (2012). Micronutrient (Zn, Cu, Fe)-gene interactions in ageing and inflammatory age-related diseases: Implications for treatments. Ageing Res. Rev. 11(2):297–319.
   PubMed Web of Science ®Google Scholar
• Morgan, E. H., Smith, G. D. and Peters, T. J. (1986). Uptake and subcellular processing of 59Fe-125I labelled transferrin by rat liver. Biochem. J. 237(1):163–173.
   PubMed Web of Science ®Google Scholar
• Muckenthaler, M., Roy, C. N., Custodio, A. O., Minana, B., deGraaf, J., Montross, L. K., Andrews, N. C. and Hentze, M. W. (2003). Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat. Genet. 34:102–107.
   PubMed Web of Science ®Google Scholar
• Myers, S. A., Nield, A. and Myers, M. (2012). Zinc Transporters, Mechanisms of Action and Therapeutic Utility: Implications for Type 2 Diabetes Mellitus. Journal of Nutrition and Metabolism. 2012:173712.
   PubMedGoogle Scholar
• Nam, H. and Knutson, M. D. (2012). Effect of dietary iron deficiency and overload on the expression of ZIP metal-ion transporters in rat liver. Biometals. 25(1):115–124.
   PubMed Web of Science ®Google Scholar
• Nemeth, E., Preza, G. C., Jung, C. L., Kaplan, J., Waring, A. J. and Ganz, T. (2006). The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study. Blood. 107(1):328–333.
   PubMed Web of Science ®Google Scholar
• Nemeth, E., Tuttle, M. S., Powelson, J., Vaughn, M. B., Donovan, A., Ward, D. M., Ganz, T. and Kaplan, J. (2004). Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 306:2090–2093.
   PubMed Web of Science ®Google Scholar
• Niereder, W. (1990). Ferritin: Iron incorporation and release. Experientia. 26:218–220.
   Google Scholar
• Nishiyama, S., Inomoto, T., Nakamura, T., Higashi, A. and Matsuda, I. (1996). Normocytic anemia with low level of TIBC, as a marker of zinc deficiency. Biomed. Res. Trace Elem. 7:175–176.
   Google Scholar
• Nishiyama, S. (1999). Zinc and IGF-I concentrations in pregnant women with anemia before and after supplementation with iron and/or zinc. J. Am. Coll. Nutr. 18:261–267.
   PubMed Web of Science ®Google Scholar
• Nittis, T. and Gitlin, J. D. (2004). Role of copper in the proteosome-mediated degradation of the multicopper oxidase hephaestin. J. Biol. Chem. 279(25):696–702.
   Google Scholar
• Olivares, M., Pizarro, F., Ruz, M. and de Romana, D. L. (2012). Acute inhibition of iron bioavailability by zinc: Studies in humans. Biometals. 25(4):657–664.
   PubMed Web of Science ®Google Scholar
• Oteiza, P. I., Clegg, M. S. and Keen, C. L. (2001). Short-term zinc deficiency affects nuclear factor-kappa B nuclear binding activity in rat testes. J. Nutr. 131(1):21–26.
   PubMed Web of Science ®Google Scholar
• Ou, O., Allen-Redpath, K., Urgast, D., Gordon, M. J., Campbell, G., Feldmann, J., Nixon, G. F., Mayer, C. D., Kwun, I. S. and Beattie, J. H. (2013). Plasma zinc's alter ego is a low-molecular.
   Google Scholar
• Palupi, L., Schultink, W., Achad, E. and Gross, R. (1997). Effective community intervention to improve hemoglobin status in preschoolers receiving once-weekly iron supplementation. Am. J. Clin. Nutr. 65:1057–1061. weight humoral factor. The FASEB Journal. 27:3672--3682.
   PubMed Web of Science ®Google Scholar
• Penny, M. E., Marin, R. M., Duran, A., Peerson, J. M., Lanata, C. F., Lonnerdal, B., Black, R. E. and Brown, K. H. (2004). Randomized controlled trial of the effect of daily supplementation with zinc or multiple micronutrients on the morbidity, growth, and micronutrient status of young Peruvian children. Am. J. Clin. Nutr. 79:457–465.
   PubMed Web of Science ®Google Scholar
• Pietrangelo, A. (2004). The ferroportin disease. Blood Cells Mol. Dis. 32(1):131–138.
   PubMed Web of Science ®Google Scholar
• Pinilla-Tenas, J. J., Sparkman, B. K., Shawki, A., Illing, A. C., Mitchell, C. J., Zhao, N., Liuzzi, J. P., Cousins, R. J., Knutson, M. D. and Mackenzie, B. (2011). Zip14 is a complex broad-scope metalion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. Am. J. Physiol. Cell Physiol. 25:115–124.
   Google Scholar
• Prasad, A. S. (2009). Zinc: Role in immunity, oxidative stress and chronic inflammation. Curr. Opin. Clin. Nutr. Metab. Care. 12(6):646–652.
   PubMed Web of Science ®Google Scholar
• Prasad, A. S., Bao, B., Beck, F. W. and Sarkar, F. H. (2001). Zinc activates NF-kappaB in HUT-78 cells. J. Lab. Clin. Med. 138(4):250–256.
   PubMed Web of Science ®Google Scholar
• Ramakrishnan, U., Cossı´o, G. T., Neufeld, M. L., Rivera, J. and Martorel, l. R. (2004). Multimicronutrient interventions but not vitamin A or iron interventions alone improve child growth: Results of 3 meta-analyses. J. Nutr. 134:2592–2602.
   PubMed Web of Science ®Google Scholar
• Ramsay, A. J., Hooper, J. D., Folgueras, A. R., Velasco, G. and López-Otín, C. (2009). Matriptase-2 (TMPRSS6): A proteolytic regulator of iron homeostasis. Haematol. Hematol. J. 94(6):840–849.
   PubMed Web of Science ®Google Scholar
• Rashed, A. A. (2011). In vitro study to determine the effect of zinc on non-heme iron absorption. Int. J. Collab. Res. Int. Med. Public Health. 3(5):354–368.
   Google Scholar
• Richardson, D. R., Chua, A. C. and Baker, E. (1999). Activation of an iron uptake mechanism from transferrin in hepatocytes by small-molecularweight iron complexes. Implications for the pathogenesis of iron-overload disease. J. Lab. Clin. Med. 133:144–151.
   PubMed Web of Science ®Google Scholar
• Rivera, S., Nemeth, E., Gabayan, V., Lopez, M., Farshidi, D. and Ganz, T. (2005). Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs. Blood. 106:2196–2199.
   PubMed Web of Science ®Google Scholar
• Sacher, A., Cohen, A. and Nelson, N. (2001). Properties of the mammalian and yeast metal-ion transporters DCT1 and Smf1p expressed in Xenopus laevis oocytes. J. Exp. Biol. 204(6):1053–1061.
   PubMed Web of Science ®Google Scholar
• Sacher, A., Cohen, A. and Nelson, N. (2004). Properties of the mammalian and yeast metalion transporters DCT1 and Smf1p expressed in Xenopus laevis oocytes. J. Exp. Biol. 204:1053–1061.
   Google Scholar
• Sanchez, M., Galy, B., Schwanhaeusser, B., Blake, J, Ivacevic, T. M., Benes, V., Selbach, M., Muckenthaler, M. U. and Hentze, W. M. (2011). Iron regulatory protein-1 and -2: transcriptome-wide definition of binding mRNAs and shaping of the cellular proteome by iron regulatory proteins. Blood. 118(22):168–179.
   Web of Science ®Google Scholar
• Scheiber-Mojdehkar, B., Sturm, B., Plank, L., Kryzer, I. and Goldenberg, H. (2003). Influence of parenteral iron preparations on non-transferrin bound iron uptake, the iron regulatory protein and the expression of ferritin and the divalent metal transporter DMT-1 in HepG2 human hepatoma cells. Biochem. Pharmacol. 65:1973–1978.
   PubMed Web of Science ®Google Scholar
• Shah, Y. M., Matsubara, T., Ito S, Yim, S. H., and Gonzalez, F. J. (2009). Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab. 9:152–164.
   PubMed Web of Science ®Google Scholar
• Shamim, A. A., Kabir, A., Merrill, R. D. et al. (2013). The effect of iron and zinc supplementation and its discontinuation on liver antioxidant status in rats fed deficient diets. Public Health Nutr. 16(8):1354–1361.
   PubMed Web of Science ®Google Scholar
• Sharp, P., Tandy, S., Yamaji, S., Tennant, J., Williams, M. and Singh Srai, S. K. (2002). Rapid regulation of divalent metal transporter (DMT1) protein but not mRNA expression by non-haem iron innhuman intestinal Caco-2 cells. Febs Lett. 510(1):71–76.
   PubMed Web of Science ®Google Scholar
• Shoham, S. and Youdim, M. B. (2002). The effects of iron deficiency and iron and zinc supplementation on rat hippocampus ferritin. J. Neural Transm. 109:1241–1256.
   PubMed Web of Science ®Google Scholar
• Smith, C. J., Makdani, D., Hegar, A., Rao, D. and Douglass, W. L. (1999). Vitamin A and zinc supplementation of preschool children. J. Am. Coll. Nutr. 18:213–222.
   PubMed Web of Science ®Google Scholar
• Silvestri, L., Pagani, A., Nai, A., De Domenico, I., Kaplan, J. and Camaschella, C. (2008). The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metabolism. 8(6):502–511.
   PubMed Web of Science ®Google Scholar
• Solomons, N. W. (1986). Competitive interaction of iron and zinc in the diet: Consequences for human nutrition. J. Nutr. 116:927–935.
   PubMed Web of Science ®Google Scholar
• Sreedhar, B. and Nair, K. M. (2005). Modulation of aconitase, metallothionein, and oxidative stress in zinc deficient rat intestine during zinc and iron repletion. Free Radic. Biol. Med. 39(8):999–1008.
   PubMed Web of Science ®Google Scholar
• Sreedhar, B., Subramaniyan, R. and Nair, K. M. (2004). A protective role for zinc on intestinal peroxidative damage during oral iron repletion. Biochem. Biophys. Res. Commun. 318:992–997.
   PubMed Web of Science ®Google Scholar
• Stuart, G. Anderson, Frazer, D., Powell, L., McCullen, M., Fletcher, L., et al. (2003). Duodenal expression of iron transport molecules in untreated haemochromatosis subjects. Gut. 52:953–959.
   PubMed Web of Science ®Google Scholar
• Tallkvist, J., Bowlus, C. L. and Lonnerdal, B. (2000). Functional and molecular responses of human intestinal Caco-2 cells to iron treatment. Am. J. Clin. Nutr. 72:770–775.
   PubMed Web of Science ®Google Scholar
• Tandy, S., Williams, M., Leggett, A., Lopez-Jimenez, M., Dedes, M., Ramesh, B., Srai, S. K. and Sharp, P. (2000). Nramp2 expression is associated with pH-dependent iron uptake across the apical membrane of human intestinal Caco-2 cells. J. Biol. Chem. 275:1023–1029.
   PubMed Web of Science ®Google Scholar
• Taylor, M. Qu, Anderson, E. R., Anderson, T., Matsubara, A., Martin, F. J., Gonzalez, Y. M. and Shah, Y. M. (2011). Hypoxia-inducible factor-2alpha mediates the adaptive increase of intestinal ferroportin during iron deficiency inmice. Gastroenterology. 140:2044–2055.
   PubMed Web of Science ®Google Scholar
• Thambiayya, K., Kaynar, A., Claudette, M., Croix, M. and Pitt, B. (2012). Functional role of intracellular labile zinc in pulmonary endothelium. Pulmonary Circulation. 2(4):443–451.
   PubMedGoogle Scholar
• Troadec, M. B., Ward, D. M., Lo, E., Kaplan, J. and De Domenico, I. (2010). Induction of FPN1 transcription by MTF-1 reveals a role for ferroportin in transition metal efflux. Blood. 116(22):4657–4664.
   PubMed Web of Science ®Google Scholar
• Van Uden, P., Kenneth, N. S., Webster, R., Müller, H. A., Mudie, S. and Rocha, S. (2011). Evolutionary conserved regulation of HIF-1β by NF-κB. Plos. Genet. 27(7):1.
   Google Scholar
• Vehik, K. and Dabelea, D. (2011). The changing epidemiology of type 1 diabetes: Why is it going through the roof? Diabetes. Metab. Res. Rev. 27:3–13.
   PubMed Web of Science ®Google Scholar
• Wang X., Zhou B. (2010). Dietary zinc absorption: A play of Zips and ZnTs in the gut. IUBMB Life. 62(3):176–182.
   PubMed Web of Science ®Google Scholar
• Wang, X., Garrick, M. D., Yang, F., Dailey, L. A., Piantadosi, C. A., and Ghio, A. J. (2005). TNF, IFN-d, and endotoxin increase expression of DMT1 in bronchial epithelial cells. Am. J. Physiol. 289:L24–L33.
   Web of Science ®Google Scholar
• Wang, C. Y., Jenkitkasemwong, S., Duarte, S., Sparkman, B. K., Shawki, A., Mackenzie, B. and Knutson, M. D. (2012). ZIP8 Is an Iron and Zinc transporter whose cell-surface expression is up-regulated by cellular Iron loading. J. Biol. Chem. 287(41):34032–34043.
   PubMed Web of Science ®Google Scholar
• Wang, C. Y. and Knutson, M. (2012). Role of the iron-import protein DMT1 (Divalent Metal Transporter 1) in liver iron uptake. Faseb. J. 26.
   Web of Science ®Google Scholar
• Wang, J. and Pantopoulos, K. (2011). Regulation of cellular iron metabolism. Biochem. J. 434:365–381.
   PubMed Web of Science ®Google Scholar
• Ward, D. and Kaplan, J. (2012). Ferroportin-mediated iron transport: Expression and regulation. Biochim. Biophys. Acta. 1823(9):1426–1433.
   PubMed Web of Science ®Google Scholar
• Weaver, B., Beattie, J. D., Kambe, T. and Andrews, K. G. (2007). Novel zinc-responsive post-transcriptional mechanisms reciprocally regulate expression of the mouse Slc39a4 and Slc39a5 zinc transporters (Zip4 and Zip5). Biol. Chem. 388(12):1301–1312.
   PubMed Web of Science ®Google Scholar
• Westin, G. and Shaffner, W. (1988). A zinc-responsive factor interacts with a metal-regulated enhancer element (MRE) of the mouse metallothionein-I gene. EMBO J. 7:3763–3770.
   PubMed Web of Science ®Google Scholar
• Weston, B. F., Brenot, A. and Caparon, M. G. (2009). The metal homeostasis protein, Lsp, of Streptococcus pyogenes is necessary for acquisition of zinc and virulence. Infect. Immun. 77:2840–2848.
   PubMed Web of Science ®Google Scholar
• Willam, C. (2014). HIF meets NF-κB signaling. Kidney Int. 85:232–234.
   PubMed Web of Science ®Google Scholar
• Wu, W., Wang, X., Zhang, W. et al. (2003). Zinc induced PTEN protein degradation through the proteasome pathway in human airway epithelial cells. J. Biol. Chem. 278:28258–28263.
   PubMed Web of Science ®Google Scholar
• Yamaji, S., Sharp, P., Ramesh, B. and Srai, S. K. (2004). Inhibition of iron transport across human intestinal epithelial cells by hepcidin. Blood. 104:2178–2180.
   PubMed Web of Science ®Google Scholar
• Yamaji, S., Tennant, J., Tandy, S., Williams, M., Srai, S. K. and Sharp, P. (2001). Zinc regulates the function and expression of the iron transporters DMT1 and IREG1 in human intestinal Caco-2 cells. FEBS Lett. 507:137–141.
   PubMed Web of Science ®Google Scholar
• Yeh, K., Yeh, M. and Glass, J. (2004). Hepcidin regulation of ferroportin 1 expression in the liver and intestine of the rat. Am. J. Physiol. Gastrointest. Liver Physiol. 286:G385–G394.
   Web of Science ®Google Scholar
• Yeh, K.-Y., Yeh, M. and Glass, J. (2011). Interactions Between Ferroportin and Hephaestin in Rat Enterocytes Are Reduced After Iron Ingestion. Gastroenterology. 141(1):292–U391.
   PubMed Web of Science ®Google Scholar
• Zangger, K., Shen, G., Oz, G., Otvos, J. D. and Armitage, I. M. (2001). Oxidative dimerization in metallothionein is a result of intermolecular disulphide bonds between cysteines in the alpha-domain. Biochem. J. 359:353–360.
   PubMed Web of Science ®Google Scholar
• Zhang, A. S. and Enns, C. A. (2009a). Iron homeostasis: recently identified proteins provide insight into novel control mechanisms. J. Biol. Chem. 284:711–715.
   PubMed Web of Science ®Google Scholar
• Zhang, A. S. and Enns, C. A. (2009b). Molecular mechanisms of normal iron homeostasis. Hematology. 207:14.
   Google Scholar
• Zhang, D. L., Hughes, R. M., Ollivierre-Wilson, H., Ghosh, M. C. and Rouault, T. A. (2009). A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression. Cell Metab. 9:461–473.
   PubMed Web of Science ®Google Scholar
• Zoller, H., Koch, R. O., Theurl, I., Obrist, P., Pietrangelo, A., Montosi, G., Haile, D. J., Vogel, W., and Weiss, G. (2001). Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload. Gastroenterology. 120(6):1412–1419.
   PubMed Web of Science ®Google Scholar