Mechanisms and regulation of intestinal iron absorption
Mechanisms and regulation of intestinal iron absorption
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DOI：
10.1006/bcmd.2002.0578
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发表时间：
2002-11-01
影响因子：
2.3
通讯作者：
Oates, PS
中科院分区：
文献类型：
--
作者：
Morgan, EH;Oates, PS
小肠的铁吸收根据身体的需要进行调节，铁缺乏时增加，铁过载时减少。有人提出，吸收效率取决于发育中的肠上皮细胞在 Lieberkuhn 隐窝中获得的铁量，这调节了肠绒毛成熟肠上皮细胞中铁转运蛋白（如 DMT1）的表达。在隐窝中，细胞通过受体介导的内吞作用从血浆转铁蛋白中摄取铁，这一过程受到血色素沉着蛋白 HFE 的影响。因此，血浆转铁蛋白结合铁的可用性以及转铁蛋白受体 (TfR1)、HFE 和 DMT1 的表达和功能都应有助于绒毛肠上皮细胞的吸收能力。在遗传正常的大鼠和小鼠、贝尔格莱德贫血 (b/b) 大鼠和 HFE 敲除小鼠中研究了铁吸收调节和机制的这些方面。 在大多数实验中，TfR1 的功能是通过静脉注射放射性标记的转铁蛋白结合铁的摄取来评估的。使用闭合的原位十二指肠环测量非血红素铁的吸收。通过原位杂交和免疫组织化学测定DMT1和TfR1的表达和细胞分布。转铁蛋白结合铁的摄取和功能性TfR1的表达主要发生在隐窝细胞中，并且与血浆铁浓度成正比。它并未因 b/b 大鼠中发生的 DMT1 突变而受损，但在 HFE 敲除小鼠中却受损。这些小鼠的铁吸收增加，但与正常小鼠一样，仍然受到铁储存水平的影响。这些结果与铁吸收的拟议调节一致，并表明 DMT1 并不是在隐窝细胞内体中运行的唯一铁转运蛋白。未能检测到隐窝细胞中的 DMT1 mRNA 或蛋白质支持了这一观点。 DMT1 mRNA 和蛋白质的表达始于隐窝-绒毛交界处，并在绒毛中部区域增加至最高水平。与对照组相比，铁缺乏症中的表达量更大，铁负荷动物中的表达量更少，并且在铁缺乏的大鼠中，大部分蛋白质存在于刷状缘膜上。在正常大鼠中，铁吸收效率与 DMT1 表达水平平行，但在 b/b 大鼠中，尽管 DMT1 存在于绒毛肠细胞中，但吸收率非常低且与膳食铁含量无关。结果证实了 DMT1 在非血红素铁吸收的摄取阶段的重要作用。当之前喂食低铁饮食的正常大鼠通过胃管给予铁丸时，十二指肠中测试剂量的铁吸收随后随着 DMT1 mRNA 和蛋白质的表达而减少，在 1 小时内开始，并在 7 小时内达到低水平。 DMT1 与刷状缘膜的边缘消失。这些结果表明，DMT1 的表达水平、细胞内分布和功能对饮食中的铁含量做出非常快速的反应，并受到储存铁水平的影响。 (C) 2002 年爱思唯尔科学（美国）。
Iron absorption from the small intestine is regulated according to the body's needs, increasing in iron deficiency and decreasing in iron overload. It has been proposed that the efficiency of absorption is determined by the amount of iron acquired by developing enterocytes when they are in the crypts of Lieberkuhn and that this regulates expression of iron transporters such as DMT1 in mature enterocytes of the intestinal villi. In the crypts the cells take up iron from plasma transferrin by receptor-mediated endocytosis, a process that is influenced by the hemochromatosis protein, HFE. Hence, the availability of plasma transferrin-bound iron and the expression and function of transferrin receptors (TfR1), HFE and DMT1 should all contribute to the absorptive capacity of villus enterocytes. These aspects of the regulation and mechanism of iron absorption were investigated in genetically normal rats and mice, and in Belgrade anemic (b/b) rats and HFE knockout mice.In most experiments the function of the TfR1 was assessed by the uptake of radiolabeled transferrin-bound iron given intravenously. Absorption of non-heme iron was measured using closed in situ duodenal loops. The expression and cellular distribution of DMT1 and TfR1 were determined by in situ hybridisation and immunohistochemistry.The uptake of transferrin-bound iron and expression of functional TfR1 was shown to occur mainly in crypt cells and to be proportional to the plasma concentration of iron. It was not impaired by the mutation of DMT1 that occurs in b/b rats but was impaired in HFE knockout mice. Iron absorption was increased in these mice but was still influenced by the level of iron stores, as in normal mice. These results are in accordance with the proposed regulation of iron absorption and suggest that DMT1 is not the only iron transporter operating within endosomes of crypt cells. This view was supported by the failure to detect DMT1 mRNA or protein in crypt cells. Expression of DMT1 mRNA and protein started at the crypt-villus junction and increased to reach highest levels in the mid-villus region. Greater expression was found in iron deficiency and less in iron loaded animals than in controls and in the iron deficient rats most of the protein was present on the brush border membrane. In normal rats the efficiency of iron absorption parallelled the level of DMT1 expression, but in b/b rats absorption was very low and independent of dietary iron content even though DMT1 was present in villus enterocytes. The results confirm the essential role of DMT1 in the uptake phase of non-heme iron absorption. When normal rats previously fed a low iron diet were given a bolus of iron by stomach tube, the subsequent absorption of iron from a test dose placed in the duodenum diminished in parallel with the expression of DMT1 mRNA and protein, commencing within 1 hour and reaching low levels by 7 hours. The margination of DMT1 to the brush border membrane disappeared. These results show the level of expression and intracellular distribution and function of DMT1 respond very quickly to the iron content of the diet as well as being affected by storage iron levels. (C) 2002 Elsevier Science (USA).