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Intestinal divalent metal‐ion transporter‐1 is critical for iron homeostasis but is not required for maintenance of Cu or Zn
Author(s) -
Shawki Ali,
Anthony Sarah R,
Nose Yasuhiro,
De Renshaw Tomasa Barrientos,
Thiele Dennis J,
Mackenzie Bryan
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1112.2
Subject(s) - dmt1 , chemistry , kidney , spleen , hemoglobin , hepcidin , medicine , iron deficiency , anemia , ferroportin , endocrinology , ferritin , transporter , biochemistry , biology , gene
Divalent metal‐ion transporter‐1 (DMT1)—the product of the SLC11A2 gene—is a widely‐expressed iron transporter that serves intestinal iron absorption and erythroid iron utilization. Whereas DMT1 exhibits reactivity with a broad range of transition metal ions, questions have arisen as to the role that DMT1 plays in the absorption of Cu and Zn. We tested the hypothesis that DMT1 is essential for the absorption of Fe, Cu, Mn, and Zn by examining hematological parameters, iron status, and tissue metal content in a mouse model lacking intestinal DMT1 (i.e. DMT1 int/int ) at age ≈ 120 days. Generation of the DMT1 int/int model, by crossing floxed DMT1 and villin‐Cre transgenic lines, was described previously [Gunshin et al (2005) J. Clin. Invest. 115 , 1258–1266]. The DMT1 int/int mouse exhibited a severe microcytic, hypochromic anemia—characterized by profound decreases in hematocrit (DMT1 int/int , 7% ± SD 2% cf. wildtype, 44% ± 4%; n = 7–9), hemoglobin concentration, mean corpuscular volume, and serum iron— accompanied by cardiac hypertrophy, splenomegaly, and severely depleted nonheme iron stores (liver, spleen). Intraperitoneal iron injection corrected the iron‐deficiency anemia phenotype of the DMT1 int/int mouse. Analysis of tissue metal content by using ICP–MS revealed strikingly decreased Fe levels in spleen, liver, heart and kidney in DMT1 int/int compared with wildtype mice. Mn content was modestly decreased in kidney and spleen but not in other tissues. We observed no changes in tissue Zn or Cu levels, except for a modest increase in spleen Cu content. Our data indicate that intestinal DMT1 is critical for iron homeostasis but is not required for maintenance of Cu or Zn status.