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Estrogen Up-Regulates Iron Transporters and Iron Storage Protein Through Hypoxia Inducible Factor 1 Alpha Activation Mediated by Estrogen Receptor β and G Protein Estrogen Receptor in BV2 Microglia Cells

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Abstract

Estrogen is a steroid hormone produced mainly by the ovaries. It has been found that estrogen could regulate iron metabolism in neurons and astrocytes in different ways. The role of estrogen on iron metabolism in microglia is currently unknown. In this study, we investigated the effect and mechanism of 17β-estrogen (E2) on iron transport proteins. We found that following E2 treatment for 24h in BV2 microglial cell lines, the iron importer divalent metal transporter 1 (DMT1) and iron exporter ferroportin 1 (FPN1) were up-regulated , iron storage protein ferritin (FT) was increased. The protein levels of iron regulatory proteins (IRPs) and hepcidin remained unchanged, but hypoxia inducible factor 1 alpha (HIF-1α) was up-regulated. Two kinds of estrogen receptor β (ERβ) antagonist G15 and G protein estrogen receptor (GPER) antagonist PHTPPcould block the effects of E2 in BV2 microglial cell lines. These results suggest that estrogen could increase the protein expressions of DMT1, FPN1, FT-L and FT-H in BV2 microglia cells, which were not related to the regulation of IRP1 and hepcidin, but to the upregulation of HIF-1α. In addition, estrogen might regulate the expressions of iron-related proteins through both ER β and GPER in BV2 microglia cells.

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Funding

National Natural Science Foundation of China, 31571054, Jun Wang, 31771124, Junxia Xie; Shandong Provincial Key Research and Development Project, 2019GSF108224, Jun Wang; Natural Science Foundation of Shandong Province, ZR2021MC116, Jun Wang.

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  1. Yan Qu and Na Li have contributed equally to this work.

Authors and Affiliations

  1. School of Basic Medicine, Qingdao University, Qingdao, 266071, China

    Yan Qu, Na Li, Danyang Zhang & Jun Wang

  2. Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, 266071, China

    Manman Xu, Junxia Xie & Jun Wang

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  1. Yan Qu
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Qu, Y., Li, N., Xu, M. et al. Estrogen Up-Regulates Iron Transporters and Iron Storage Protein Through Hypoxia Inducible Factor 1 Alpha Activation Mediated by Estrogen Receptor β and G Protein Estrogen Receptor in BV2 Microglia Cells. Neurochem Res 47, 3659–3669 (2022). https://doi.org/10.1007/s11064-022-03658-1

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