Estrogen contributes to regulating iron metabolism through governing ferroportin signaling via an estrogen response element

Qian, Yi; Yin, Chunyang; Chen, Yue; Zhang, Shuping; Jiang, Li; Wang, Fudi; Zhao, Meirong; Liu, Sijin

doi:10.1016/j.cellsig.2015.01.017

Cited by 39 publications

(38 citation statements)

References 66 publications

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“…Inconsistent with these findings however was the observation that E2 suppresses FPN expression [43] and that it enhances hepcidin synthesis though a GPR30-BMP6-depeddent signaling in hepatocytes and the liver-derived Hep2 cells [44]. This is in direct conflict with previous work, which has shown that elevated levels of E2 associate with increased FPN expression [12].…”

Section: Discussioncontrasting

confidence: 56%

Estrogen-Dependent Downregulation of Hepcidin Synthesis Induces Intracellular Iron Efflux in Cancer Cells In Vitro

Shafarin¹,

Bajbouj²,

Serafy³

et al. 2016

Biol Med (Aligarh)

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It is well accepted that intracellular iron overload that associate with various forms of cancer fuels tumor mutagenesis and growth. Hence, iron chelation therapy is being increasingly used to minimize iron overload in cancer patients despite significant safety and efficacy concerns. Mounting evidence suggests that estrogen (E2) downregulates hepcidin synthesis and increases serum iron concentration. It is postulated therefore that, by downregulating hepcidin synthesis, E2 may maintain ferroportin integrity and enhance intracellular iron efflux. Here, MCF-7 and SKOV-3 cancer cells treated with increasing concentrations (5, 10 and 20 nM) of E2 were assessed for intracellular labile iron content, the expression of hepcidin, ferroportin, and transferrin receptors 1 and 2 along with cell viability at different time points post treatment. In MCF-7 cells, E2 treatment resulted in a significant reduction in hepcidin synthesis, most noticeably at the 20 nM/24 h dose, a significant increase in ferroportin expression and a marked decrease in transferrin receptors 1 and 2 expression. E2-treated cells also showed reduced intracellular labile iron content most evidently at 20 nM/48 h dose and reduced viability especially at 20 nM/72 h dose. E2-treated SKOV-3 showed slightly reduced intracellular labile iron content, reduced expression of hepcidin and significantly increased expression of TFR1 but not TFR2; FPN expression was overall similar to that of controls. The effects of E2 on intracellular iron metabolism in SKOV-3 were most evident at 5 nM/24 h dose. These findings suggest that E2 treatment induces intracellular iron efflux, which may minimize intracellular iron overload in cancer cells; disrupted expression of transferrin receptor 1 and/or 2 may help sustain a low intracellular iron environment.

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Section: Discussioncontrasting

confidence: 56%

Estrogen-Dependent Downregulation of Hepcidin Synthesis Induces Intracellular Iron Efflux in Cancer Cells In Vitro

Shafarin¹,

Bajbouj²,

Serafy³

et al. 2016

Biol Med (Aligarh)

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“…Estrogen may influence iron metabolism by modulating the hepcidin-ferroportin axis, which fundamentally governs global iron absorption, distribution, utilization and egress. A repression of ferroportin at the transcriptional level by estrogen was observed in another study and could result in intracellular iron accumulation (66, 67). …”

Section: Discussionmentioning

confidence: 72%

MRI Characterization in the Acute Phase of Experimental Subarachnoid Hemorrhage

Guo

Wilkinson

Thompson

et al. 2016

Transl. Stroke Res.

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A number of mechanisms have been proposed for the early brain injury after subarachnoid hemorrhage (SAH). In this study, we investigated the radiographic characteristics and influence of gender on early brain injury after experimental SAH. SAH was induced by endovascular perforation in male and female rats. Magnetic resonance imaging was performed in a 7.0-T Varian MR scanner at 24 hours after SAH. The occurrence and size of T2 lesions, ventricular dilation and white matter injury (WMI) was determined on T2 weighted images (T2WI). The effects of SAH on heme oxygenase-1 and fibrin/fibrinogen were examined by Western blotting and immunohistochemistry. SAH severity was assessed using a MRI grading system and neurological function was evaluated according to a modified Garcia’s scoring system. T2-hyperintensity areas and enlarged ventricles were observed in T2WI coronal sections 24 hours after SAH. The overall incidence of T2-lesions, WMI and hydrocephalus was 54, 20 and 63%, respectively. Female rats had a higher incidence of T2-hyperintensity lesions and hydrocephalus, as well as larger T2 lesion volumes and higher average ventricular volume. SAH rats graded at 3-4 (our previously validated MRI grading scale) had larger T2 lesion volumes, more hydrocephalus and worse neurological function compared with those graded at 0-2. In conclusion, T2-lesion, WMI and hydrocephalus were the most prevalent MRI characteristics 24 hours after experimental SAH. The T2-lesion area matched with fibrinogen/fibrin positive staining in the acute phase of SAH. SAH induced more severe brain injury in females compared to males in the acute phase of SAH.

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“…Additionally, transcriptional regulation of ferroportin could be studied in more detail using bioinformatics analyses of promoter sequence motifs and reporter gene assays in cell culture. Several transcription factors have been implicated in transcriptional regulation of ferroportin, including hypoxia inducible factor 2 (HIF2 α ), nuclear factor erythroid (Nrf2), metal-regulatory transcription factor 1 (MTF-1) and estrogen receptor [76]. Identification of the regulatory mechanisms that predominate in vivo would allow interfering with transcriptional regulation of ferroportin during inflammation and hence lead to a better understanding of its importance in inflammation, host-pathogen interactions and cancer.…”

Section: Discussionmentioning

confidence: 99%

Modelling Systemic Iron Regulation during Dietary Iron Overload and Acute Inflammation: Role of Hepcidin-Independent Mechanisms

et al. 2017

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Systemic iron levels must be maintained in physiological concentrations to prevent diseases associated with iron deficiency or iron overload. A key role in this process plays ferroportin, the only known mammalian transmembrane iron exporter, which releases iron from duodenal enterocytes, hepatocytes, or iron-recycling macrophages into the blood stream. Ferroportin expression is tightly controlled by transcriptional and post-transcriptional mechanisms in response to hypoxia, iron deficiency, heme iron and inflammatory cues by cell-autonomous and systemic mechanisms. At the systemic level, the iron-regulatory hormone hepcidin is released from the liver in response to these cues, binds to ferroportin and triggers its degradation. The relative importance of individual ferroportin control mechanisms and their interplay at the systemic level is incompletely understood. Here, we built a mathematical model of systemic iron regulation. It incorporates the dynamics of organ iron pools as well as regulation by the hepcidin/ferroportin system. We calibrated and validated the model with time-resolved measurements of iron responses in mice challenged with dietary iron overload and/or inflammation. The model demonstrates that inflammation mainly reduces the amount of iron in the blood stream by reducing intracellular ferroportin transcription, and not by hepcidin-dependent ferroportin protein destabilization. In contrast, ferroportin regulation by hepcidin is the predominant mechanism of iron homeostasis in response to changing iron diets for a big range of dietary iron contents. The model further reveals that additional homeostasis mechanisms must be taken into account at very high dietary iron levels, including the saturation of intestinal uptake of nutritional iron and the uptake of circulating, non-transferrin-bound iron, into liver. Taken together, our model quantitatively describes systemic iron metabolism and generated experimentally testable predictions for additional ferroportin-independent homeostasis mechanisms.

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Estrogen contributes to regulating iron metabolism through governing ferroportin signaling via an estrogen response element

Cited by 39 publications

References 66 publications

Estrogen-Dependent Downregulation of Hepcidin Synthesis Induces Intracellular Iron Efflux in Cancer Cells In Vitro

Estrogen-Dependent Downregulation of Hepcidin Synthesis Induces Intracellular Iron Efflux in Cancer Cells In Vitro

MRI Characterization in the Acute Phase of Experimental Subarachnoid Hemorrhage

Modelling Systemic Iron Regulation during Dietary Iron Overload and Acute Inflammation: Role of Hepcidin-Independent Mechanisms

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