Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis
Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis
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肝转铁蛋白在全身铁稳态和肝铁死亡中发挥作用
DOI：
10.1182/blood.2019002907
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发表时间：
2020-08-06
期刊：
影响因子：
20.3
通讯作者：
Wang, Fudi
中科院分区：
文献类型：
--
作者：
Yu, Yingying;Jiang, Li;Wang, Fudi
尽管血清中富含金属结合蛋白转铁蛋白（由Trf基因编码）主要在肝脏中合成，但其在肝脏中的功能在很大程度上是未知的。在这里，我们产生了肝细胞特异性Trf基因敲除小鼠（Trf-LKO），这是可行的和生育能力，但有受损的红细胞生成和改变铁代谢。此外，喂食高铁饮食的Trf-LKO小鼠增加了它们对发生铁中毒诱导的肝纤维化的易感性。重要的是，我们发现用铁凋亡抑制剂ferrostatin-1治疗Trf-LKO小鼠有效地挽救了由高膳食铁或四氯化碳（CCl 4）注射诱导的肝纤维化。此外，在Trf-LKO小鼠中删除肝脏Slc 39 a14表达显著降低了肝脏铁积累，从而减少了由高铁饮食或CCl 4注射诱导的铁中毒介导的肝纤维化。最后，我们发现，肝硬化患者血清转铁蛋白和肝转铁蛋白水平显着降低，以及较高的水平，肝铁和脂质过氧化反应，与健康对照组相比。综上所述，这些数据表明，肝转铁蛋白在维持肝功能方面起保护作用，为预防铁中毒诱导的肝纤维化提供了可能的治疗靶点。
Although the serum-abundant metal-binding protein transferrin (encoded by the Trf gene) is synthesized primarily in the liver, its function in the liver is largely unknown. Here, we generated hepatocyte-specific Trf knockout mice (Trf-LKO), which are viable and fertile but have impaired erythropoiesis and altered iron metabolism. Moreover, feeding Trf-LKO mice a high-iron diet increased their susceptibility to developing ferroptosis-induced liver fibrosis. Importantly, we found that treating Trf-LKO mice with the ferroptosis inhibitor ferrostatin-1 potently rescued liver fibrosis induced by either high dietary iron or carbon tetrachloride (CCl4) injections. In addition, deleting hepatic Slc39a14 expression in Trf-LKO mice significantly reduced hepatic iron accumulation, thereby reducing ferroptosis-mediated liver fibrosis induced by either a high-iron diet or CCl4 injections. Finally, we found that patients with liver cirrhosis have significantly lower levels of serum transferrin and hepatic transferrin, as well as higher levels of hepatic iron and lipid peroxidation, compared with healthy control subjects. Taken together, these data indicate that hepatic transferrin plays a protective role in maintaining liver function, providing a possible therapeutic target for preventing ferroptosis-induced liver fibrosis.