Estrogen regulates iron homeostasis through governing hepatic hepcidin expression via an estrogen response element

Abstract

a b s t r a c t a r t i c l e i n f oIron is essential for the human being, involving in oxygen transport, energy metabolism and DNA synthesis. Iron homeostasis is tightly governed by the hepcidin-ferroportin axis, of which hepcidin is the master regulator. Excess iron is associated with various diseases including osteopenia and osteoporosis, which are closely related to the alternation of the endogenous estrogen level. To verify the biological effect of estrogen on iron metabolism, we established a mouse model of estrogen deficiency by ovariectomy. We demonstrated that the hemoglobin content and serum iron level decreased, whereas the tissue iron level in liver and spleen increased in the ovariectomized mice. Moreover, the transcription of hepatic hepcidin was elevated in ovariectomized mice compared to the control mice. We further demonstrated that there was an estrogen response element (ERE) in the promoter region of the hepcidin gene. The assay using the luciferase reporter system confirmed the existence of a functional ERE in the hepcidin promoter, as the estradiol treatment reduced hepcidin expression in cells transfected with ERE-intact construct, with no response to estradiol in cells transfected with ERE-devoid construct. In conclusion, estrogen greatly contributes to iron homeostasis by regulating hepatic hepcidin expression directly through a functional ERE in the promoter region of hepcidin gene. These findings might help build a better understanding towards the etiology of postmenopausal osteoporosis accompanied by excess tissue iron (such as iron retention of osteoclasts in bone) under estrogen deficiency.

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

“…As shown in Fig. 7B, the transcriptional activity of Pro-ERE was reduced by 20% upon E2 treatment, whereas the response to E2 was thoroughly lost in Pro-EREΔ transfected cells, similar to the mechanism of E2-mediated repression of hepcidin, in our previous study [23]. These findings therefore suggested that the putative ERE (−376/−388 bp) functionally responded to E2.…”

“…Hou and colleagues from our research group previously identified an ERE within the promoter of hepcidin, and this ERE was responsible for E2-induced suppression of hepcidin expression in hepatocytes [23]. Therefore, we assumed that the promoter of FPN might also harbor a similar estrogen response site.…”

“…Hepatocytes have relatively high level of FPN on the plasma membrane [39]. Representative cell models of hepatocytes, such as HepG2 and SMMC-7721 cells, were conventionally used in estrogen-related studies [22,23]. Thus, we looked into the alteration of FPN expression upon E2 in HepG2 and SMMC-7721 cells.…”

“…8C). As our previous study showed that hepcidin could also be down-regulated by E2 [23], we subsequently inspected the hepcidin expression. In agreement with the previous finding, the absence of estrogen greatly enhanced the mRNA level of hepcidin by nearly 2 fold (Fig.…”

“…For example, reduction of monthly blood loss would certainly help to retain body iron [17]. Recent studies from our research group and another group have uncovered the regulation of hepcidin by estrogen, linking estrogen to iron homeostasis [22,23]. Nonetheless, the impact of estrogen on iron metabolism is still elusive, and specifically, no insight has been gained for the potential regulation of estrogen on FPN.…”