Iron is critical for many processes including oxygen transport and erythropoiesis. Transcriptomic analysis demonstrates that HIF-2a induced following iron deficiency in the intestine. However, beyond divalent metal transporter 1 (DMT1), ferroportin 1 (Fpn1) and duodenal cytochrome b (Dcytb), no other genes/pathways have been critically assessed with respects to their importance in intestinal iron absorption. Ferritinophagy is associated with cargo specific autophagic breakdown of ferritin and subsequent release of iron. We show here that nuclear receptor co-activator 4 (NCOA4)-mediated intestinal ferritinophagy is integrated to systemic iron demand via HIF-2a. Duodenal NCOA4 expression is regulated by HIF-2a during high systemic iron demands. Moreover, overexpression of intestinal HIF-2a is sufficient to activate NCOA4 and promote lysosomal degradation of ferritin. Promoter analysis revealed NCOA4 as a direct HIF-2a target. To demonstrate the importance of intestinal HIF-2a/ferritinophagy axis in systemic iron homeostasis, whole body and intestine-specific NCOA4-null mouse lines were assessed. These analyses demonstrate an iron sequestration in the enterocytes, and significantly high tissue ferritin levels in the dietary iron deficiency and acute hemolytic anemia models. Together, our data suggests efficient ferritinophagy is critical for intestinal iron absorption and systemic iron homeostasis.

中文翻译：

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肠铁蛋白吞噬受HIF-2调节，对于全身铁稳态是必不可少的

铁对许多过程至关重要，包括氧气运输和促红细胞生成。转录组学分析表明，HIF-2a引起肠道铁缺乏症。但是，除了二价金属转运蛋白1（DMT1），铁转运蛋白1（Fpn1）和十二指肠细胞色素b（Dcytb），就其在肠道铁吸收中的重要性而言，尚无其他基因/途径被严格评估过。铁蛋白吞噬与货物特异的铁蛋白自噬分解和随后的铁释放有关。我们在这里显示，核受体共激活因子4（NCOA4）介导的肠道铁蛋白吞噬通过HIF-2a整合到系统性铁需求中。全身高铁需求时，HIF-2a调节十二指肠NCOA4的表达。此外，肠道HIF-2a的过表达足以激活NCOA4并促进铁蛋白的溶酶体降解。启动子分析显示NCOA4是直接的HIF-2a靶标。为了证明肠道HIF-2a /铁蛋白吞噬轴在系统性铁稳态中的重要性，评估了全身和肠道特异性NCOA4-无效小鼠系。这些分析表明在饮食中的铁缺乏和急性溶血性贫血模型中，肠细胞中的铁被隔离，组织铁蛋白水平显着升高。总之，我们的数据表明有效的铁素体吞咽对于肠道铁的吸收和全身铁的稳态至关重要。评估了全身和肠道特异性NCOA4无效小鼠系。这些分析表明，膳食细胞铁缺乏和急性溶血性贫血模型中肠细胞中铁被隔离，组织铁蛋白水平显着升高。总之，我们的数据表明有效的铁素体吞咽对于肠道铁吸收和全身铁稳态至关重要。评估了全身和肠道特异性NCOA4无效小鼠系。这些分析表明在饮食中的铁缺乏和急性溶血性贫血模型中，肠细胞中的铁被隔离，组织铁蛋白水平显着升高。总之，我们的数据表明有效的铁素体吞咽对于肠道铁吸收和全身铁稳态至关重要。