HFE and ALK3 act in the same signaling pathway.
HFE and ALK3 act in the same signaling pathway.
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DOI：
10.1016/j.freeradbiomed.2020.08.023
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发表时间：
2020-08
影响因子：
7.4
通讯作者：
L. Traeger;J. Schnittker;D. Y. Dogan;D. Oguama;T. Kuhlmann;M. Muckenthaler;J. Krijt;E. Urzica;A. Steinbicker
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文献类型：
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作者：
L. Traeger;J. Schnittker;D. Y. Dogan;D. Oguama;T. Kuhlmann;M. Muckenthaler;J. Krijt;E. Urzica;A. Steinbicker
铁调素缺乏通过增加膳食铁摄取和储存细胞释放铁导致铁过载。Hfe中最常见的突变导致铁调素表达减少，从而导致铁过载。最近的研究结果表明，HFE主要通过BMP I型受体ALK 3激活铁调素表达。在这里，我们研究了HFE是否专门利用ALK 3或其他信号传导机制。我们产生了Hfe和肝细胞特异性Alk 3双重缺陷的小鼠，并将这些双敲除小鼠的铁过载表型与单肝细胞特异性Alk 3缺陷或Hfe敲除小鼠进行了比较。双Hfe −/−/肝Alk 3fl/fl;与单肝细胞特异性Alk 3缺陷小鼠相比，Alb-Creknockouts产生了相似的铁过载表型，其特点是血清铁水平、组织铁含量和铁调素水平相似。与Alk 3fl/fl小鼠相比，Alk 3fl/fl;Alb-Cremice的HFE蛋白水平增加，这是由铁过载引起的，而不是由Alk 3缺乏引起的。这些数据通过遗传学手段提供了证据，1。HFE仅使用BMP I型受体ALK 3来诱导hepcidin表达，2.铁超载诱导HFE蛋白表达，进一步强调了HFE的铁传感功能。
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 ofHfeand hepatocyte-specific Alk3 and compared the iron overload phenotypes of these double knockout mice to single hepatocyte-specificAlk3deficient orHfeknockout mice. DoubleHfe−/−/hepaticAlk3fl/fl;Alb-Creknockouts develop a similar iron overload phenotype compared to single hepatocyte-specificAlk3deficient mice hallmarked by serum iron levels, tissue iron content and hepcidin levels of similar grades. HFE protein levels were increased inAlk3fl/fl;Alb-Cremice compared toAlk3fl/flmice, which was caused by iron overload – and not byAlk3deficiency. 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.