The FBXL5-IRP2 Axis Is Integral to Control of Iron Metabolism In Vivo
The FBXL5-IRP2 Axis Is Integral to Control of Iron Metabolism In Vivo
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DOI：
10.1016/j.cmet.2011.07.011
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发表时间：
2011-09-07
期刊：
影响因子：
29
通讯作者：
Nakayama, Keiichi I.
中科院分区：
文献类型：
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作者：
Moroishi, Toshiro;Nishiyama, Masaaki;Nakayama, Keiichi I.
铁调节蛋白2(IRP2)的铁依赖降解是维持适当的细胞内铁浓度的关键事件。尽管FBXL5(F盒和富含亮氨酸的重复蛋白5)被认为介导了这种降解，但FBXL5在体内铁稳态控制中的作用一直知之甚少。我们现在发现，缺乏FBXL5的小鼠会在子宫中死亡，这与铁的过度积累有关。这种胚胎死亡是通过额外的IRP2消融来防止的，这表明IRP2降解受损是Fbx15(-/-)小鼠死亡的主要原因。我们还发现，肝脏特异的Fbx15基因缺失导致肝脏和全身铁稳态的破坏，导致脂肪性肝炎的发生。肝脏特异性突变小鼠在喂食高铁饮食时死于急性肝功能衰竭。因此，我们的结果揭示了FBXL5在确保细胞适当的铁供应方面的重要作用。
Iron-dependent degradation of iron-regulatory protein 2 (IRP2) is a key event for maintenance of an appropriate intracellular concentration of iron. Although FBXL5 (F box and leucine-rich repeat protein 5) is thought to mediate this degradation, the role of FBXL5 in the control of iron homeostasis in vivo has been poorly understood. We have now found that mice deficient in FBXL5 died in utero, associated with excessive iron accumulation. This embryonic mortality was prevented by additional ablation of IRP2, suggesting that impaired IRP2 degradation is primarily responsible for the death of Fbxl5(-/-) mice. We also found that liver-specific deletion of Fbxl5 resulted in deregulation of both hepatic and systemic iron homeostasis, leading to the development of steatohepatitis. The liver-specific mutant mice died with acute liver failure when fed a high-iron diet. Thus, our results uncover a major role for FBXL5 in ensuring an appropriate supply of iron to cells.