Estrogen regulates hepcidin expression via GPR30-BMP6-dependent signaling in hepatocytes.
Estrogen regulates hepcidin expression via GPR30-BMP6-dependent signaling in hepatocytes.
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DOI：
10.1371/journal.pone.0040465
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Tamaki T
中科院分区：
文献类型：
--
作者：
Ikeda Y;Tajima S;Izawa-Ishizawa Y;Kihira Y;Ishizawa K;Tomita S;Tsuchiya K;Tamaki T
铁调素是一种肝源性铁调节蛋白，在铁代谢中起着至关重要的作用。众所周知，体内铁储存存在性别差异;然而，性类固醇激素对铁代谢的影响尚未完全了解。我们专注于女性性激素雌激素对hepcidin表达的影响。首先，在体内研究中，采用卵巢切除（OVX）和假手术小鼠来研究雌激素对hepcidin表达的影响。与假手术小鼠相比，去卵巢小鼠肝脏中的铁调素表达降低。在OVX小鼠，骨形态蛋白-6（BMP 6），铁调素的调节剂，也被发现在肝脏下调，而铁转运蛋白（FPN），铁输出蛋白，在十二指肠上调。OVX小鼠血清和肝脏铁浓度均高于假手术小鼠。在体外研究中，17β-雌二醇（E2）以浓度依赖的方式增加HepG 2细胞hepcidin mRNA的表达。雌激素受体抑制剂ICI 182720不抑制E2诱导的肝铁调素上调;相反，铁调素表达增加ICI 182720。E2和ICI 182720表现出与G蛋白偶联受体30（GPR 30）（7-跨膜雌激素受体）的激动剂作用。G1，GPR 30激动剂，上调hepcidin的表达，和GPR 30 siRNA治疗废除E2诱导的hepcidin的表达。GPR 30沉默可抑制E2诱导的BMP 6表达。最后，补充E2和G1都恢复了OVX小鼠肝铁调素和BMP 6表达的降低，并逆转了十二指肠FPN表达的增加。相反，血清铁调素在OVX小鼠中升高，这在E2和G1小鼠中逆转。因此，雌激素通过GPR 30-BMP 6依赖性机制参与铁调素表达，为雌激素在铁代谢中的作用提供了新的见解。
Hepcidin, a liver-derived iron regulatory protein, plays a crucial role in iron metabolism. It is known that gender differences exist with respect to iron storage in the body; however, the effects of sex steroid hormones on iron metabolism are not completely understood. We focused on the effects of the female sex hormone estrogen on hepcidin expression. First, ovariectomized (OVX) and sham-operated mice were employed to investigate the effects of estrogen on hepcidin expression in an in vivo study. Hepcidin expression was decreased in the livers of OVX mice compared to the sham-operated mice. In OVX mice, bone morphologic protein-6 (BMP6), a regulator of hepcidin, was also found to be downregulated in the liver, whereas ferroportin (FPN), an iron export protein, was upregulated in the duodenum. Both serum and liver iron concentrations were elevated in OVX mice relative to their concentrations in sham-operated mice. In in vitro studies, 17β-estradiol (E2) increased the mRNA expression of hepcidin in HepG2 cells in a concentration-dependent manner. E2-induced hepatic hepcidin upregulation was not inhibited by ICI 182720, an inhibitor of the estrogen receptor; instead, hepcidin expression was increased by ICI 182720. E2 and ICI 182720 exhibit agonist actions with G-protein coupled receptor 30 (GPR30), the 7-transmembrane estrogen receptor. G1, a GPR30 agonist, upregulated hepcidin expression, and GPR30 siRNA treatment abolished E2-induced hepcidin expression. BMP6 expression induced by E2 was abolished by GPR30 silencing. Finally, both E2 and G1 supplementation restored reduced hepatic hepcidin and BMP6 expression and reversed the augmentation of duodenal FPN expression in the OVX mice. In contrast, serum hepcidin was elevated in OVX mice, which was reversed in these mice with E2 and G1. Thus, estrogen is involved in hepcidin expression via a GPR30-BMP6-dependent mechanism, providing new insight into the role of estrogen in iron metabolism.
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影响因子：
29
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通讯作者：
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