Glycochenodeoxycholate Affects Iron Homeostasis via Up-Regulating Hepcidin Expression.
Glycochenodeoxycholate Affects Iron Homeostasis via Up-Regulating Hepcidin Expression.
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糖鹅脱氧胆酸盐通过上调Hepcidin表达影响铁稳态。
DOI：
10.3390/nu14153176
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发表时间：
2022-08-02
期刊：
影响因子：
5.9
通讯作者：
Ren, Fa-zheng
中科院分区：
文献类型：
--
作者：
Wang, Long-jiao;Zhao, Guo-ping;Wang, Xi-fan;Liu, Xiao-xue;Li, Yi-xuan;Qiu, Li-li;Wang, Xiao-yu;Ren, Fa-zheng
铁调素表达增加是慢性肾脏病（CKD）患者铁稳态失衡的重要因素。最近的研究表明，血清类固醇水平异常可能导致铁调素升高。糖鹅去氧胆酸盐（GCDCA）是一种类固醇，在CKD患者中显著升高。然而，GCDCA和hepcidin之间的相关性尚未阐明。在本研究中，CKD患者血清铁水平降低，铁调素水平升高。此外，发现肾病患者的GCDCA浓度高于健康受试者。以HepG 2细胞为研究对象，观察GCDCA对Hepcidin的影响。结果表明，在200 μM GCDCA处理下，hepcidin的表达比对照增加了近两倍。SMAD 1/5/8磷酸化水平显著升高，而STAT 3和CREBH无明显变化。GCDCA可诱导FXR的表达，继而诱导SMAD 1/5/8的上调因子BMP 6和ALK 3的转录和表达。因此，GCDCA是hepcidin的潜在调节剂，其可能通过触发FXR和BMP 6/ALK 3-SMAD信号通路起作用。此外，40只C57/BL 6小鼠用100 mg/kg/d、200 mg/kg/d和300 mg/kg/d GCDCA处理，以研究其对体内铁调素的影响。200 mg/kg/d和300 mg/kg/d GCDCA处理的小鼠血清铁调素水平升高，而血红蛋白和血清铁水平降低。类似地，FXR介导的SMAD信号通路也负责激活肝脏中的铁调素。总之，可以得出结论，GCDCA可以诱导hepcidin的表达并降低血清铁水平，其中FXR激活相关的SMAD信号转导是GCDCA的主要靶点。因此，异常的GCDCA水平表明铁稳态失衡的潜在风险。
Increasing hepcidin expression is a vital factor in iron homeostasis imbalance among patients with chronic kidney disease (CKD). Recent studies have elucidated that abnormal serum steroid levels might cause the elevation of hepcidin. Glycochenodeoxycholate (GCDCA), a steroid, is significantly elevated in patients with CKD. However, the correlation between GCDCA and hepcidin has not been elucidated. Decreased serum iron levels and increased hepcidin levels were both detected in patients with CKD in this study. Additionally, the concentrations of GCDCA in nephropathy patients were found to be higher than those in healthy subjects. HepG2 cells were used to investigate the effect of GCDCA on hepcidin in vitro. The results showed that hepcidin expression increased by nearly two-fold against control under 200 μM GCDCA treatment. The phosphorylation of SMAD1/5/8 increased remarkably, while STAT3 and CREBH remained unchanged. GCDCA triggered the expression of farnesoid X receptor (FXR), followed with the transcription and expression of both BMP6 and ALK3 (upward regulators of SMAD1/5/8). Thus, GCDCA is a potential regulator for hepcidin, which possibly acts by triggering FXR and the BMP6/ALK3-SMAD signaling pathway. Furthermore, 40 C57/BL6 mice were treated with 100 mg/kg/d, 200 mg/kg/d, and 300 mg/kg/d GCDCA to investigate its effect on hepcidin in vivo. The serum level of hepcidin increased in mice treated with 200 mg/kg/d and 300 mg/kg/d GCDCA, while hemoglobin and serum iron levels decreased. Similarly, the FXR-mediated SMAD signaling pathway was also responsible for activating hepcidin in liver. Overall, it was concluded that GCDCA could induce the expression of hepcidin and reduce serum iron level, in which FXR activation-related SMAD signaling was the main target for GCDCA. Thus, abnormal GCDCA level indicates a potential risk of iron homeostasis imbalance.
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影响因子：
3.7
作者：
Ikeda Y;Tajima S;Izawa-Ishizawa Y;Kihira Y;Ishizawa K;Tomita S;Tsuchiya K;Tamaki T
通讯作者：
Tamaki T
DOI：
10.1126/science.1176639
发表时间：
2009-08-14
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Vecchi C;Montosi G;Zhang K;Lamberti I;Duncan SA;Kaufman RJ;Pietrangelo A
通讯作者：
Pietrangelo A
影响因子：
64.5
作者：
Muckenthaler MU;Rivella S;Hentze MW;Galy B
通讯作者：
Galy B
影响因子：
13.6
作者：
Babitt, Jodie L.;Lin, Herbert Y.
通讯作者：
Lin, Herbert Y.
影响因子：
5
作者：
Huang, Ying-Hsien;Chuang, Jiin-Haur;Chen, Chao-Long
通讯作者：
Chen, Chao-Long