Fasting Increases Iron Export by Modulating Ferroportin 1 Expression Through the Ghrelin/GHSR1α/MAPK Pathway in the Liver
Fasting Increases Iron Export by Modulating Ferroportin 1 Expression Through the Ghrelin/GHSR1α/MAPK Pathway in the Liver
复制标题
禁食通过肝脏中的 Ghrelin/GHSR1 α/MAPK 途径调节铁转运蛋白 1 的表达来增加铁输出
DOI：
10.1007/s12011-020-02114-x
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发表时间：
2020-03-25
影响因子：
3.9
通讯作者：
Wang, Guohua
中科院分区：
文献类型：
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作者：
Luo, Qianqian;Hu, Jianan;Wang, Guohua
肝脏有助于维持体内铁平衡和控制身体对禁食的适应。尽管之前的研究表明铁和Ghrelin在小鼠和人类中都存在负相关，但禁食或Ghrelin是否对肝脏中的铁稳态有功能影响仍有待探索。在这项研究中，我们研究了禁食和Ghrelin对小鼠肝脏和培养肝细胞Fpn1、转铁蛋白受体1(TfR1)和铁蛋白轻链(Ft-L)蛋白表达的调节作用，以及对Ghrelin、海普西丁、Ghrelin O-酰基转移酶(山羊)和生长激素促分泌素受体1α(GHSR1α)基因表达的调节。我们的体内研究结果表明，禁食显著上调了小鼠肝脏中Ghrelin、山羊和GHSR1α的基因表达，以及Ghrelin、Fpn1和Ft-L的蛋白水平，但不能上调TfR1mRNA的表达。有趣的是，禁食后海普西丁的mRNA表达没有明显变化。同时，在培养的肝细胞中，Ghrelin显著增加Fpn1的蛋白表达，但不增加Ft-L和TfR1的蛋白表达，并显著增强ERK的磷酸化。此外，用PERK抑制剂或GHSR1α拮抗剂对培养的肝细胞进行预处理，可消除Ghrelin对Fpn1表达和ERK磷酸化的影响。我们的发现证实，禁食通过Ghrelin/GHSR1α/MAPK信号通路上调Fpn1的表达，增加了肝脏的铁出口。
The liver is contributed to maintaining body iron homeostasis and controlling of body adaptation to fasting. Although previous studies implied a negative relationship between iron and ghrelin in both mice and humans, it remains to be explored whether fasting or ghrelin has a functional effect on iron homeostasis in the liver. In this study, we examined the roles of fasting and ghrelin in modulating the protein expression of Fpn1, transferrin receptor 1 (TfR1), and ferritin light chain (Ft-L), as well as the mRNA expression of ghrelin, hepcidin, ghrelin O-acyltransferase (GOAT), and growth hormone secretagogue receptor 1 alpha (GHSR1 alpha) in mouse liver and cultured hepatocytes. Our in vivo results suggested that fasting significantly upregulated the mRNA expression of ghrelin, GOAT, and GHSR1 alpha, as well as the protein levels of ghrelin, Fpn1, and Ft-L, but not TfR1, in mouse liver. Interestingly, mRNA expression of hepcidin did not change significantly after fasting. Meanwhile, in cultured hepatocytes, ghrelin significantly increased the protein expression of Fpn1 but not Ft-L and TfR1 and significantly enhanced ERK phosphorylation. Furthermore, the pretreatment of cultured hepatocytes with either a pERK inhibitor or a GHSR1 alpha antagonist abolished the effects of ghrelin on Fpn1 expression and ERK phosphorylation. Our findings confirmed that fasting increases iron export in the liver by upregulating Fpn1 expression through the ghrelin/GHSR1 alpha/MAPK signaling pathway.