Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese

American Journal of Physiology - Gastrointestinal and Liver Physiology

Volumn 309, Issue 8, 2015, Pages G635-G647

  Shawki, Ali ^a   Anthony, Sarah R ^a   Nose, Yasuhiro ^b   Engevik, Melinda A ^a   Niespodzany, Eric J ^a   Barrientos, Tomasa ^b   Öhrvik, Helena ^b,c   Worrell, Roger T ^a   Thiele, Dennis J ^b   Mackenzie, Bryan ^a  

^a UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE   (United States)

^b DUKE UNIVERSITY MEDICAL CENTER   (United States)

^c UPPSALA UNIVERSITY   (Sweden)

Author keywords

Copper absorption; Iron deficiency; Iron deficiency anemia; Iron refractive iron deficiency anemia; Manganese absorption; SLC11A2; Zinc metabolism

Indexed keywords

COPPER; HEPCIDIN; IRON; IRON 59; MANGANESE; MESSENGER RNA; NATURAL RESISTANCE ASSOCIATED MACROPHAGE PROTEIN 2; CATION TRANSPORT PROTEIN; CTR1 PROTEIN, MOUSE; SOLUTE CARRIER FAMILY 11- (PROTON-COUPLED DIVALENT METAL ION TRANSPORTERS), MEMBER 2; ZINC;

ADULT; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; GENE EXPRESSION; INTESTINE ABSORPTION; INTESTINE FUNCTION; IRON ABSORPTION; IRON BLOOD LEVEL; IRON DEFICIENCY ANEMIA; IRON STORAGE; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; ANIMAL; GENE EXPRESSION REGULATION; GENETICS; HOMEOSTASIS; KNOCKOUT MOUSE; METABOLISM; PATHOLOGY; PHYSIOLOGY;

ANEMIA, HYPOCHROMIC; ANIMALS; CATION TRANSPORT PROTEINS; COPPER; GENE EXPRESSION REGULATION; HOMEOSTASIS; INTESTINAL ABSORPTION; IRON; MANGANESE; MICE; MICE, KNOCKOUT; ZINC;

EID: 84945242847     PISSN: 01931857     EISSN: 15221547     Source Type: Journal    
DOI: 10.1152/ajpgi.00160.2015     Document Type: Article

References (60)

1. Arredondo M, Mendiburo MJ, Flores S, Singleton ST, Garrick MD. Mouse divalent metal transporter 1 is a copper transporter in HEK293 cells. Biometals 27: 115-123, 2014.
2. Arredondo M, Muñoz P, Mura CV, Núñez MT. DMT1, a physiologically relevant apical Cu1 transporter of intestinal cells. Am J Physiol Cell Physiol 284: C1525-C1530, 2003.
3. Beard JL. Why iron deficiency is important in infant development. J Nutr 138: 2534-2536, 2008.
4. Beutler E. Disorders of iron metabolism. In: Williams Hematology, edited by Kaushansky K, Beutler E, Seligsohn U, Lichtman MA, Kipps TJ, Prchal JT. New York: McGraw-Hill Medical, 2010.
5. Canonne-Hergaux F, Gruenheid S, Ponka P, Gros P. Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood 93: 4406-4417, 1999.
6. Cesta MF. Normal structure, function, and histology of the spleen. Toxicol Pathol 34: 455-465, 2006.
7. Chua ACG, Morgan EH. Manganese metabolism is impaired in the Belgrade laboratory rat. J Comp Physiol [B] 167: 361-369, 1997.
8. Collins JF. Gene chip analyses reveal differential genetic responses to iron deficiency in rat duodenum and jejunum. Biol Res 39: 25-37, 2006.
9. Collins JF, Franck CA, Kowdley KV, Ghishan FK. Identification of differentially expressed genes in response to dietary iron deprivation in rat duodenum. Am J Physiol Gastrointest Liver Physiol 288: G964-G971, 2005.
10. Cousins RJ. Gastrointestinal factors influencing zinc absorption and homeostasis. Int J Vitam Nutr Res 80: 243-248, 2010.
11. Curran-Everett D. Multiple comparisons: philosophies and illustrations. Am J Physiol Regul Integr Comp Physiol 279: R1-R8, 2000.
12. Darshan D, Frazer DM, Anderson GJ. Molecular basis of iron-loading disorders. Expert Rev Mol Med 12: e36, 2010.
13. Dufner-Beattie J, Weaver BP, Geiser J, Bilgen M, Larson M, Xu W, Andrews GK. The mouse acrodermatitis enteropathica gene Slc39a4 (Zip4) is essential for early development and heterozygosity causes hypersensitivity to zinc deficiency. Hum Mol Genet 16: 1391-1399, 2007.
14. Edwards JA, Hoke JE. Defect of intestinal mucosal iron uptake in mice with hereditary microcytic anemia. Proc Soc Exp Biol Med 141: 81-84, 1972.
15. el Marjou F, Janssen KP, Chang BHJ, Li M, Hindie V, Chan L, Louvard D, Chambon P, Metzger D, Robine S. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis 39: 186-193, 2004.
16. Espinoza A, Le BS, Olivares M, Pizarro F, Ruz M, Arredondo M. 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: 281-286, 2012.
17. Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC. Nramp2 is mutated in the anemic Belgrade (b) rat: Evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA 95: 1148-1153, 1998.
18. Fleming MD, Trenor CC, Su MA, Foernzler D, Beier DR, Dietrich WF, Andrews NC. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet 16: 383-386, 1997.
19. Fleming RE, Ponka P. Iron overload in human disease. N Eng J Med 366: 348-359, 2012.
20. Franich NR, Fitzsimons HL, Fong DM, Klugmann M, During MJ, Young D. AAV vector-mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington’s disease. Mol Ther 16: 947-956, 2008.
21. Ganz T. Systemic iron homeostasis. Physiol Rev 93: 1721-1741, 2013.
22. Gunshin H, Fujiwara Y, Custodio ÁO, Direnzo C, Robine S, Andrews NC. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest 115: 1258-1266, 2005.
23. Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388: 482-488, 1997.
24. Gunshin H, Starr CN, Direnzo C, Fleming MD, Jin J, Greer EL, Sellers VM, Galica SM, Andrews NC. Cybrd1 (duodenal cytochrome b) is not necessary for dietary iron absorption in mice. Blood 106: 2879-2883, 2005.
25. Guthrie GJ, Aydemir TB, Troche C, Martin AB, Chang SM, Cousins RJ. Influence of ZIP14 (slc39A14) on intestinal zinc processing and barrier function. Am J Physiol Gastrointest Liver Physiol 308: G171-G178, 2015.
26. Hubert N, Hentze MW. Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: Implications for regulation and cellular function. Proc Natl Acad Sci USA 99: 12345-12350, 2002.
27. Illing AC, Shawki A, Cunningham CL, Mackenzie B. Substrate profile and metal-ion selectivity of human divalent metal-ion transporter-1. J Biol Chem 287: 30485-30496, 2012.
28. Jeong J, Eide DJ. The SLC39 family of zinc transporters. Mol Aspects Med 34: 612-619, 2013.
29. Jiang L, Garrick MD, Garrick LM, Zhao L, Collins JF. Divalent metal transporter 1 (Dmt1) mediates copper transport in the duodenum of iron-deficient rats and when overexpressed in iron-deprived HEK-293 cells. J Nutr 143: 1927-1933, 2013.
30. Knöpfel M, Zhao L, Garrick MD. Transport of divalent transition-metal ions is lost in small-intestinal tissue of b/b Belgrade rats. Biochemistry 44: 3454-3465, 2005.
31. Knutson MD. Steap proteins: Implications for iron and copper metabolism. Nutr Rev 65: 335-340, 2007.
32. Lee J, Peña MM, Nose Y, Thiele DJ. Biochemical characterization of the human copper transporter Ctr1. J Biol Chem 277: 4380-4387, 2002.
33. Lee J, Petris MJ, Thiele DJ. Characterization of mouse embryonic cells deficient in the Ctr1 high affinity copper transporter: Identification of a Ctr1-independent copper transport system. J Biol Chem 277: 40253- 40259, 2002.
34. Lin C, Zhang Z, Wang T, Chen C, James Kang Y. Copper uptake by DMT1: A compensatory mechanism for CTR1 deficiency in human umbilical vein endothelial cells. Metallomics 7: 1285-1289, 2015.
35. Liuzzi JP, Aydemir F, Nam H, Knutson MD, Cousins RJ. Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc Natl Acad Sci USA 103: 13612-13617, 2006.
36. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2CT method. Methods 25: 402-408, 2001.
37. Mackenzie B, Garrick MD. Iron imports. II. Iron uptake at the apical membrane in the intestine. Am J Physiol Gastrointest Liver Physiol 289: G981-G986, 2005.
38. Mackenzie B, Ujwal ML, Chang MH, Romero MF, Hediger MA. Divalent metal-ion transporter DMT1 mediates both H-coupled Fe2+ transport and uncoupled fluxes. Pflügers Arch 451: 544-558, 2006.
39. McKie AT, Barrow D, Latunde-Dada GO, Rolfs A, Sager G, Mudaly E, Mudaly M, Richardson C, Barlow D, Bomford A, Peters TJ, Raja KB, Shirali S, Hediger MA, Farzaneh F, Simpson RJ. An ironregulated ferric reductase associated with the absorption of dietary iron. Science 291: 1755-1759, 2001.
40. McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F, Hediger MA, Hentze MW, Simpson RJ. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5: 299-309, 2000.
41. Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth MP. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet 41: 478-481, 2009.
42. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306: 2090-2093, 2004.
43. Nose Y, Kim BE, Thiele DJ. Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function. Cell Metab 4: 235-244, 2006.
44. Nose Y, Wood LK, Kim BE, Prohaska JR, Fry RS, Spears JW, Thiele DJ. Ctr1 is an apical copper transporter in mammalian epithelial cells in vivo that is controlled at the level of protein stability. J Biol Chem 285: 32385-32392, 2010.
45. Ohgami RS, Campagna DR, Greer EL, Antiochos B, McDonald A, Chen J, Sharp JJ, Fujiwara Y, Barker JE, Fleming MD. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet 37: 1264-1269, 2005.
46. Ohgami RS, Campagna DR, McDonald A, Fleming MD. The Steap proteins are metalloreductases. Blood 108: 1388-1394, 2006.
47. Okazaki Y, Ma Y, Yeh M, Yin H, Li Z, Yeh KY, Glass J. DMT1 (IRE) expression in intestinal and erythroid cells is regulated by peripheral benzodiazepine receptor-associated protein 7. Am J Physiol Gastrointest Liver Physiol 302: G1180-G1190, 2012.
48. Pinilla-Tenas JJ, Sparkman BK, Shawki A, Illing AC, Mitchell CJ, Zhao N, Liuzzi JP, Cousins RJ, Knutson MD, Mackenzie B. Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. Am J Physiol Cell Physiol 301: C862-C871, 2011.
49. Prakash S, Shawki A, Niespodzany E, Mackenzie B. Intestinal divalent metal-ion transporter-1 is required for iron homeostasis in the neonatal mouse (Abstract). FASEB J 29: 1011. 5, 2015.
50. Ramakrishnan U. Prevalence of micronutrient malnutrition worldwide. Nutr Rev 60: S46-S52, 2002.
51. Said HM, Blair JA, Lucas ML, Hilburn ME. Intestinal surface acid microclimate in vitro and in vivo in the rat. J Lab Clin Med 107: 420-424, 1986.
52. Shawki A, Knight PB, Maliken BD, Niespodzany EJ, Mackenzie B. H_-coupled divalent metal-ion transporter-1: Functional properties, physiological roles and therapeutics. Curr Top Membr 70: 169-214, 2012.
53. Tabuchi M, Tanaka N, Nishida-Kitayama J, Ohno H, Kishi F. Alternative splicing regulates the subcellular localization of divalent metal transporter 1 isoforms. Mol Biol Cell 13: 4371-4387, 2002.
54. Thompson K, Molina RM, Brain JD, Wessling-Resnick M. Belgrade rats display liver iron loading. J Nutr 136: 3010-3014, 2006.
55. Torrance JD, Bothwell TH. Tissue iron stores. In: Iron, edited by Cook JD. New York: Churchill Livingstone, 1980.
56. Wang CY, Knutson MD. Hepatocyte divalent metal-ion transporter-1 is dispensable for hepatic iron accumulation and non-transferrin-bound iron uptake in mice. Hepatology 58: 788-798, 2013.
57. Wang CY, Jenkitkasemwong S, Duarte S, Sparkman BK, Shawki A, Mackenzie B, Knutson MD. ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. J Biol Chem 287: 34032-34043, 2012.
58. Wang K, Zhou B, Kuo YM, Zemansky J, Gitschier J. A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am J Hum Genet 71: 66-73, 2002.
59. Wyman S, Simpson RJ, McKie AT, Sharp PA. Dcytb (Cybrd1) functions as both a ferric and a cupric reductase in vitro. FEBS Lett 582: 1901-1906, 2008.
60. Zoller H, Koch RO, Theurl I, Obrist P, Pietrangelo A, Montosi G, Haile DJ, Vogel W, Weiss G. Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload. Gastroenterology 120: 1412-1419, 2001.