Modulation of the HIF2α-NCOA4 axis in enterocytes attenuates iron loading in a mouse model of hemochromatosis
Modulation of the HIF2α-NCOA4 axis in enterocytes attenuates iron loading in a mouse model of hemochromatosis
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DOI：
10.1182/blood.2021013452
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发表时间：
2022-04-22
期刊：
影响因子：
20.3
通讯作者：
Shah, Yatrik M.
中科院分区：
文献类型：
--
作者：
Das, Nupur K.;Jain, Chesta;Shah, Yatrik M.
肠铁吸收在增加对铁的全身需求期间被激活。研究得最多的例子是缺铁性贫血，它会增加肠道对铁的吸收。有趣的是，肠道对贫血的反应与铁过载疾病非常相似，因为这两种疾病都激活了一个转录程序，通过转录因子缺氧诱导因子2 α（HIF 2 α）导致铁的过度吸收。然而，途径选择性靶向的精氨酸介导的铁超载仍然未知。核受体辅激活因子4（NCOA 4）是铁蛋白自噬分解和随后释放铁的关键货物受体，在称为铁蛋白自噬的过程中。我们的工作表明，NCOA 4介导的肠道铁蛋白吞噬通过HIF 2 α整合到系统铁需求中。为了证明肠HIF 2 α/铁蛋白吞噬轴在全身铁稳态中的重要性，产生并评估了全身和精氨酸特异性NC 0A 4（-/-）小鼠系。分析显示，肠和全身对缺铁的反应在肠NCOA 4破坏后没有改变。然而，在血色素沉着症的小鼠模型中，肠NCOA 4的消融对铁过载具有保护作用。因此，NCOA 4可以被选择性地靶向用于管理铁过载疾病，而不破坏参与对全身性铁缺乏的响应的生理过程。
Intestinal iron absorption is activated during increased systemic demand for iron. The best-studied example is iron deficiency anemia, which increases intestinal iron absorption. Interestingly, the intestinal response to anemia is very similar to that of iron overload disorders, as both the conditions activate a transcriptional program that leads to a hyperabsorption of iron via the transcription factor hypoxia-inducible factor 2 alpha (HIF2 alpha). However, pathways for selective targeting of intestine-mediated iron overload remain unknown. Nuclear receptor coactivator 4 (NCOA4) is a critical cargo receptor for autophagic breakdown of ferritin and the subsequent release of iron, in a process termed ferritinophagy. Our work demonstrates that NCOA4-mediated intestinal ferritinophagy is integrated into systemic iron demand via HIF2 alpha. To demonstrate the importance of the intestinal HIF2 alpha/ferritinophagy axis in systemic iron homeostasis, whole-body and intestine-specific NCOA4(-/-) mouse lines were generated and assessed. The analyses revealed that the intestinal and systemic response to iron deficiency was not altered after disruption of intestinal NCOA4. However, in a mouse model of hemochromatosis, ablation of intestinal NCOA4 was protective against iron overload. Therefore, NCOA4 can be selectively targeted for the management of iron overload disorders without disrupting the physiological processes involved in the response to systemic iron deficiency.