title: Estrogen contributes to regulating iron metabolism through governing ferroportin signaling via an estrogen response element.
abstract: Ferroportin (FPN) is the only known iron exporter in mammalian cells, and is universally expressed in most types of cells. FPN signaling plays a crucial role in maintaining iron homeostasis through governing the level of intracellular iron. Serum iron storage is conversely related with the estrogen level in the female bodies, and women in post-menopause are possibly subjected to iron retention. However, the potential effects of estrogen on iron metabolism are not clearly understood. Here, FPN mRNA transcription in all selected estrogen receptor positive (ER+) cells was significantly reduced upon 17β-estradiol (E2) treatment; and this inhibitory effect could be attenuated by ER antagonist tamoxifen. Likewise, in murine bone marrow-derived macrophages (BMDMs), FPN reduction with elevated intracellular iron (reflected by increased ferritin) was observed in response to E2; however, ferritin level barely responded to E2 in FPN-null BMDMs. The observation of inhibition of FPN mRNA expression was not replicated in ER(-) cells upon E2. A functional estrogen response element (ERE) was identified within the promoter of FPN, and this ERE was responsible for the suppressive effect of E2 on FPN expression. Moreover, ovariectomized (OVX) and sham-operated (SHAM) mice were used to further confirm the in vitro finding. The expression of hepatic FPN was induced in OVX mice, compared to that in the SHAM mice. Taken together, our results demonstrated that estrogen is involved in regulating FPN expression through a functional ERE on its promoter, providing additional insights into a vital role of estrogen in iron metabolism.
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou 310032, China.
authors: Yi
authors: Y
authors: Qian
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
authors: Chunyang
authors: C
authors: Yin
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China.
authors: Yue
authors: Y
authors: Chen
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors: Shuping
authors: S
authors: Zhang
authors: Department of Nutrition, School of Public Health, Institute of Nutrition and Food Safety, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang 310027, China.
authors: Li
authors: L
authors: Jiang
authors: Department of Nutrition, School of Public Health, Institute of Nutrition and Food Safety, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang 310027, China.
authors: Fudi
authors: F
authors: Wang
authors: College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou 310032, China. Electronic address: zhaomr@zjut.edu.cn.
authors: Meirong
authors: M
authors: Zhao
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China. Electronic address: sjliu@rcees.ac.cn.
authors: Sijin
authors: S
authors: Liu
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D020218:Response Elements; D015398:Signal Transduction; D014158:Transcription, Genetic; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D004967:Estrogens; D012333:RNA, Messenger; D000098742:Ferroportin; D007501:Iron
keywords: Estrogen; Estrogen response element; Ferroportin; Iron; Ovariectomy