Hepatocyte divalent metal-ion transporter-1 is dispensable for hepatic iron accumulation and non-transferrin-bound iron uptake in mice

摘要

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 if 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 ⁵⁹Fe-labeled ferric citrate (for NTBI) or ⁵⁹Fe-transferrin into the plasma of Dmt1^liv/liv and Dmt1^flox/flox mice and measured the uptake of ⁵⁹Fe 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 ZIP14 (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.ConclusionHepatocyte 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.