Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, University of Muenster, Muenster, Germany.
Institute of Neuropathology, University Hospital Muenster, University of Muenster, Muenster, Germany.
Free Radic Biol Med. 2020 Nov 20;160:501-505. doi: 10.1016/j.freeradbiomed.2020.08.023. Epub 2020 Aug 27.
Hepcidin deficiency leads to iron overload by increased dietary iron uptake and iron release from storage cells. The most frequent mutation in Hfe leads to reduced hepcidin expression and thereby causes iron overload. Recent findings suggested that HFE activates hepcidin expression predominantly via the BMP type I receptor ALK3. Here, we investigated whether HFE exclusively utilizes ALK3 or other signaling mechanisms also. We generated mice with double deficiency of Hfe and hepatocyte-specific Alk3 and compared the iron overload phenotypes of these double knockout mice to single hepatocyte-specific Alk3 deficient or Hfe knockout mice. Double Hfe/hepatic Alk3;Alb-Cre knockouts develop a similar iron overload phenotype compared to single hepatocyte-specific Alk3 deficient mice hallmarked by serum iron levels, tissue iron content and hepcidin levels of similar grades. HFE protein levels were increased in Alk3;Alb-Cre mice compared to Alk3 mice, which was caused by iron overload - and not by Alk3 deficiency. The data provide evidence by genetic means that 1. HFE exclusively uses the BMP type I receptor ALK3 to induce hepcidin expression and 2. HFE protein expression is induced by iron overload, which further emphasizes the iron sensing function of HFE.
亚铁调素缺乏通过增加膳食铁的摄取和储存细胞中铁的释放导致铁过载。HFE 最常见的突变导致亚铁调素表达减少，从而导致铁过载。最近的研究结果表明，HFE 通过 BMP Ⅰ型受体 ALK3 主要激活铁调素的表达。在这里，我们研究了 HFE 是否仅利用 ALK3 或其他信号机制。我们生成了肝细胞特异性 Alk3 双缺失的 Hfe 缺失小鼠，并将这些双敲除小鼠与单肝细胞特异性 Alk3 缺失或 Hfe 敲除小鼠的铁过载表型进行了比较。与单肝细胞特异性 Alk3 缺失小鼠相比，Hfe/肝 Alk3;Alb-Cre 双敲除小鼠表现出相似的铁过载表型，其特征为血清铁水平、组织铁含量和铁调素水平相似。与 Alk3 小鼠相比，Alk3;Alb-Cre 小鼠中的 HFE 蛋白水平升高，这是由铁过载引起的，而不是由 Alk3 缺乏引起的。这些数据通过遗传手段提供了证据，表明 1. HFE 仅使用 BMP Ⅰ型受体 ALK3 来诱导铁调素表达，2. HFE 蛋白表达是由铁过载诱导的，这进一步强调了 HFE 的铁感应功能。
