Apolipoprotein E deficiency induces a progressive increase in tissue iron contents with age in mice

Abstract

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.

Keywords: Apolipoprotein E knock-out (ApoE(−/-)) mice; Extracellular regulated protein kinases (Erk); Ferroportin 1 (Fpn1); Hepcidin; Iron in liver and spleen; Nuclear factor erythroid 2-related factor-2 (Nrf2); Transferrin receptor 1 (TfR1).