Association of both iron/hepcidin and apolipoprotein E (ApoE) with development of Alzheimer disease (AD) and atherosclerosis led us to hypothesize that ApoE might be required for body iron homeostasis. Here, we demonstrated that ApoE knock-out (KO) induced a progressive accumulation of iron with age in the liver and spleen of mice. Subsequent investigations showed that the increased iron in the liver and spleen was due to phosphorylated extracellular regulated protein kinases (pERK) mediated up-regulation of transferrin receptor 1 (TfR1), and nuclear factor erythroid 2-related factor-2 (Nrf2)-dependent down-regulation of ferroportin 1. Furthermore, replenishment of ApoE could partially reverse the iron-related phenotype in ApoE KO mice. The findings imply that ApoE may be essential for body iron homeostasis and also suggest that clinical late-onset diseases with unexplained iron abnormality may partly be related to deficiency or reduced expression of ApoE.

铁/铁调素和载脂蛋白E（ApoE）与阿尔茨海默氏病（AD）和动脉粥样硬化的关系，使我们推测，体内铁稳态可能需要ApoE。在这里，我们证明了ApoE敲除（KO）会随着年龄的增长在小鼠肝脏和脾脏中引起铁的逐步积累。随后的研究表明，肝脏和脾脏中铁的增加是由于磷酸化的细胞外调节蛋白激酶（pERK）介导的转铁蛋白受体1（TfR1）上调，以及核因子红系2相关因子2（Nrf2）依赖性下调铁转运蛋白1。此外，补充ApoE可以部分逆转ApoE KO小鼠中铁相关的表型。