Hepatocyte divalent metal-ion transporter-1 is dispensable for hepatic iron accumulation and non-transferrin-bound iron uptake in mice.
Hepatocyte divalent metal-ion transporter-1 is dispensable for hepatic iron accumulation and non-transferrin-bound iron uptake in mice.
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DOI：
10.1002/hep.26401
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发表时间：
2013-08
期刊：
影响因子：
--
通讯作者：
Knutson MD
中科院分区：
文献类型：
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作者：
Wang CY;Knutson MD
二价金属离子转运蛋白-1（DMT 1）是肠道和发育中的红系细胞摄取铁所必需的。DMT 1也存在于肝脏中，在肝脏中，它参与了转铁蛋白结合铁（TBI）和非转铁蛋白结合铁（NTBI）的摄取，这在铁过载期间出现在血浆中。为了验证DMT 1是肝脏铁摄取所必需的假设，我们检查了在肝细胞中选择性失活的Dmt 1基因（Dmt 1 liv/liv）的小鼠。我们发现，Dmt 1 liv/liv小鼠和对照组（Dmt 1flox/flox）在肝脏铁浓度或铁状态的其他参数方面没有差异。为了确定肝细胞DMT 1是否是肝铁积累所必需的，我们将Dmt 1 liv/liv小鼠与Hfe−/−和低转铁蛋白血症（Trfhpx/hpx）小鼠杂交，这些小鼠出现肝铁过载。双突变体Hfe−/−; Dmt1liv/liv和Trfhpx/hpx;发现Dmt 1 liv/liv小鼠的肝脏铁积累量与其各自的对照组相似。为了直接评估DMT 1在NTBI和TBI摄取中的作用，我们将59 Fe标记的柠檬酸铁（用于NTBI）或59 Fe-转铁蛋白注射到Dmt 1 liv/liv和Dmt 1flox/flox小鼠的血浆中，并测量肝脏对59 Fe的摄取。Dmt 1 liv/liv小鼠的肝脏NTBI摄取没有受到损害，但TBI摄取降低了40%。转铁蛋白受体1和2以及ZIP 14（ZRT/IRT样蛋白14）的肝脏水平也可能参与铁的吸收，但在Dmt 1 liv/liv小鼠中不受影响。此外，在喂食缺铁饮食的Dmt 1 liv/liv小鼠中，肝脏铁水平不受影响。肝细胞DMT 1与肝脏铁积累和NTBI摄取有关。虽然肝细胞DMT 1是肝TBI摄取所必需的部分，但在Dmt 1 liv/liv小鼠中，肝铁水平未受影响，这表明该途径对肝脏的铁经济性贡献较小。
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 (Dmt1liv/liv). We found that Dmt1liv/liv mice and controls (Dmt1flox/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 Dmt1liv/liv mice with Hfe−/− and hypotransferrinemic (Trfhpx/hpx) mice that develop hepatic iron overload. Double-mutant Hfe−/−;Dmt1liv/liv and Trfhpx/hpx;Dmt1liv/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 Dmt1liv/liv and Dmt1flox/flox mice and measured the uptake of 59Fe by the liver. Dmt1liv/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 Dmt1liv/liv mice. Additionally, liver iron levels were unaffected in Dmt1liv/liv mice fed an iron-deficient diet. 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 Dmt1liv/liv mice, suggesting that this pathway is a minor contributor to the iron economy of the liver.