The function of heme-regulated eIF2α kinase in murine iron homeostasis and macrophage maturation

Liu, Sijin; Suragani, Rajasekhar Nvs; Wang, Fudi; Han, Anping; Zhao, Wanting; Andrews, Nancy C.; Chen, Jane-Jane

doi:10.1172/jci32084

Cited by 84 publications

(93 citation statements)

References 53 publications

(73 reference statements)

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“…Thereafter, the medium containing PMA was replaced with fresh medium for further experiments. Murine bone marrow-derived macrophages (BMDMs) were isolated and cultured as previously described [25].…”

Section: Cell Culturementioning

confidence: 99%

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

Qian

Yin

Chen

et al. 2015

Cellular Signalling

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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.

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Section: Cell Culturementioning

confidence: 99%

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

Qian

Yin

Chen

et al. 2015

Cellular Signalling

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“…The hepatic and splenic iron content was assessed as previously described (S. Liu et al, 2007Liu et al, , 2008.…”

Section: Iron Parametersmentioning

confidence: 99%

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

Hou

Zhang

Wang

et al. 2012

Gene

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162

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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.

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“…Hepatic iron content was assessed as previously described (Liu et al, 2007(Liu et al, , 2008. Briefly, the specimens of liver were digested by the acid solution for 72 h at 65°C.…”

Section: Iron Parametersmentioning

confidence: 99%

Hepcidin deficiency undermines bone load-bearing capacity through inducing iron overload

Sun

Guo

Yin

et al. 2014

Gene

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Osteoporosis is one of the leading disorders among aged people. Bone loss results from a number of physiological alterations, such as estrogen decline and aging. Meanwhile, iron overload has been recognized as a risk factor for bone loss. Systemic iron homeostasis is fundamentally governed by the hepcidin-ferroportin regulatory axis, where hepcidin is the key regulator. Hepcidin deficiency could induce a few disorders, of which iron overload is the most representative phenotype. However, there was little investigation of the effects of hepcidin deficiency on bone metabolism. To this end, hepcidin-deficient (Hamp1 −/− ) mice were employed to address this issue. Our results revealed that significant iron overload was induced in Hamp1 −/− mice. Importantly, significant decreases of maximal loading and maximal bending stress were found in Hamp1 −/− mice relative to wildtype (WT) mice.Moreover, the levels of the C-telopeptide of type I collagen (CTX-1) increased in Hamp1 −/− mice. Therefore, hepcidin deficiency resulted in a marked reduction of bone load-bearing capacity likely through enhancing bone resorption, suggesting a direct correlation between hepcidin deficiency and bone loss. Targeting hepcidin or the pathway it modulates may thus represent a therapeutic for osteopenia or osteoporosis.

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The function of heme-regulated eIF2α kinase in murine iron homeostasis and macrophage maturation

Cited by 84 publications

References 53 publications

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

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

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

Hepcidin deficiency undermines bone load-bearing capacity through inducing iron overload

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