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Hepatocyte divalent metal‐ion transporter‐1 is dispensable for hepatic iron accumulation and non‐transferrin‐bound iron uptake in mice
Author(s) -
Wang ChiaYu,
Knutson Mitchell D.
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26401
Subject(s) - dmt1 , transferrin , hepatocyte , chemistry , medicine , transferrin receptor , transporter , biochemistry , endocrinology , iron deficiency , biology , anemia , in vitro , gene
Divalent metal‐ion transporter‐1 (DMT1) is required for iron uptake by the intestine and developing erythroid cells. DMT1 is also present in the liver, where it has been implicated in the uptake of transferrin‐bound iron (TBI) and non‐transferrin‐bound iron (NTBI), which appears in the plasma during iron overload. To test the hypothesis that DMT1 is required for hepatic iron uptake, we examined mice with the Dmt1 gene selectively inactivated in hepatocytes ( Dmt1 liv/liv ). We found that Dmt1 liv/liv mice and controls ( Dmt1 flox/flox ) did not differ in terms of hepatic iron concentrations or other parameters of iron status. To determine whether hepatocyte DMT1 is required for hepatic iron accumulation, we crossed Dmt1 liv/liv mice with Hfe − / − and hypotransferrinemic ( Trf hpx/hpx ) mice that develop hepatic iron overload. Double‐mutant Hfe − / − Dmt1 liv/liv and Trf hpx/hpx ;Dmt1 liv/liv mice were found to accumulate similar amounts of hepatic iron as did their respective controls. To directly assess the role of DMT1 in NTBI and TBI uptake, we injected 59 Fe‐labeled ferric citrate (for NTBI) or 59 Fe‐transferrin into plasma of Dmt1 liv/liv and Dmt1 flox/flox mice and measured uptake of 59 Fe by the liver. Dmt1 liv/liv mice displayed no impairment of hepatic NTBI uptake, but TBI uptake was 40% lower. Hepatic levels of transferrin receptors 1 and 2 and ZRT/IRT‐like protein 14, which may also participate in iron uptake, were unaffected in Dmt1 liv/liv mice. Additionally, liver iron levels were unaffected in Dmt1 liv/liv mice fed an iron‐deficient diet. Conclusion : Hepatocyte DMT1 is dispensable for hepatic iron accumulation and NTBI uptake. Although hepatocyte DMT1 is partially required for hepatic TBI uptake, hepatic iron levels were unaffected in Dmt1 liv/liv mice, suggesting that this pathway is a minor contributor to the iron economy of the liver. (H epatology 2013;58:788–798)