Intestinal iron uptake determined by divalent metal transporter is enhanced in HFE-deficient mice with hemochromatosis
Intestinal iron uptake determined by divalent metal transporter is enhanced in HFE-deficient mice with hemochromatosis
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DOI：
10.1053/gast.2001.24050
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发表时间：
2001-05-01
期刊：
影响因子：
29.4
通讯作者：
Cox, TM
中科院分区：
文献类型：
--
作者：
Griffiths, WJH;Sly, WS;Cox, TM
背景和目标：十二指肠二价金属转运蛋白（DMT 1）信使RNA的过度表达发生在血色素沉着症和HFE基因敲除小鼠，表明DMT 1介导铁的吸收增强，然而，功能性DMT 1蛋白的表达增加尚未得到证实。我们研究了DMT 1和粘膜铁摄取缺陷在HFE基因敲除小鼠中的作用。研究方法：在HFE基因敲除小鼠和野生型小鼠配对之间，比较了小肠粘膜对Fe-59的体外单向铁摄取。DMT 1特异性抗体用于阻断铁转运和定量十二指肠蛋白表达。结果如下：与野生型相比，HFE基因敲除的小鼠对3.5-450 μ mol/L亚铁离子的吸收大大增强，Fe 2+转运的表观Vmax加倍（P < 0.01），以Fe 3+形式供应，仅在小于或等于18 μ mol/L的HFE敲除中摄取增强，此时铁几乎完全被粘膜铁还原酶转化为Fe 2+，DMT 1抗体降低了HFE敲除中粘膜Fe 2+转运的表观Vmax至野生型对照值以下（P < 0.02）;免疫反应性粘膜DMT 1蛋白在HFE基因敲除组中增加近2倍结论：HFE基因的缺失可上调DMT 1转运蛋白的功能，并通过此机制促进亚铁的摄取; DMT 1还介导在生理浓度下呈现的三价铁还原后的摄取增加。
Background & Aims: Overexpression of duodenal divalent metal transporter (DMT1) messenger RNA occurs in hemochromatosis and HFE-knockout mice, suggesting that DMT1 mediates enhanced absorption of iron; however, increased expression of functional DMT1 protein has yet to be substantiated. We examined the role of DMT1 and the mucosal iron uptake defect in HFE-knockout mice. Methods: Unidirectional iron uptake of Fe-59 by small intestinal mucosa in vitro was compared between matched pairs of HFE-knockout and wild-type mice. DMT1-specific antibodies were used to block iron transport and to quantify duodenal protein expression. Results: Ferrous iron uptake at 3.5-450 mu mol/L was greatly enhanced in HFE-knockouts compared with wildtype, the apparent V-max for Fe2+ transport being doubled (P < 0.01), Supplied as Fe3+, uptake was only enhanced in HFE-knockouts at less than or equal to 18 mu mol/L, when the iron was almost completely converted to Fe2+ by mucosal ferrireductases, DMT1 antibody reduced the apparent V-max for mucosal Fe2+ transport in HFE-knockouts to below wildtype control values (P < 0.02); immunoreactive mucosal DMT1 protein was increased nearly 2-fold in HFE-knockouts (P < 0.01), Conclusions: Disruption of the HFE gene up-regulates functional DMT1 transporters and enhances uptake of ferrous iron by this mechanism; DMT1 also mediates increased uptake after reduction of ferric iron presented at physiological concentrations.