Hepcidin is down-regulated in alcoholic liver injury: Implications for the pathogenesis of alcoholic liver disease
Hepcidin is down-regulated in alcoholic liver injury: Implications for the pathogenesis of alcoholic liver disease
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DOI：
10.1111/j.1530-0277.2006.00002.x
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发表时间：
2006-01-01
影响因子：
3.2
通讯作者：
Fletcher, LM
中科院分区：
文献类型：
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作者：
Bridle, KR;Cheung, TK;Fletcher, LM
背景：已知酒精性肝病与铁稳态异常有关，铁代谢本身受肝源性肽铁调素调节。 CCAAT 增强子结合蛋白 α (C/EBP α) 和白细胞介素 6 (IL-6) 均已被证明可调节铁调素基因转录。目的：通过使用体内和体外酒精性肝损伤模型测量铁调素和 C/EBPα mRNA 的表达，研究酒精诱导的铁稳态紊乱的机制。方法：对雄性大鼠配对饲喂酒精流质饮食 12 周。使用铁调素和 C/EBP α 的特异性引物对肝组织进行 RT-PCR。还在用 50 mM 乙醇、200 μM 乙醛和/或 20 ng/ml IL-6 处理的分离肝细胞、HuH-7 细胞和 HepG2 细胞中测定了酒精对 Hepcidin 和 C/EBP α 基因表达的影响。 结果：与配对喂养对照相比，酒精喂养的大鼠中 Hepcidin 和 C/EBPα mRNA 表达显着降低（6 倍 p < 0.001，与对照组相比，酒精喂养的大鼠的肝脏脂质过氧化水平分别降低了 2.2 倍（p < 0.0002），并且肝脏脂质过氧化增加了 32.5%（p < 0.05）。在 50 mM 乙醇存在下培养的细胞中，铁调素基因表达没有显着改变。 IL-6 刺激 24 小时后，肝细胞中的铁调素表达增加了 4 倍，HuH-7 细胞中的铁调素表达增加了 9 倍。乙醇 (50mM) 可减弱 HuH-7 细胞中 IL-6 诱导的铁调素表达增加（增加 9 倍至 4 倍），但在肝细胞中则不然。乙醛对培养细胞中的铁调素基因表达没有影响。 结论：体内显示的铁调素和 C/EBPα 基因表达下调意味着铁感应受到干扰，导致酒精性肝病中出现的肝铁苷沉着症，可能是通过涉及 IL-6 信号级联的机制实现的。
Background: Alcoholic liver disease is known to be associated with abnormal iron homeostasis, and iron metabolism itself is regulated by the liver-derived peptide hepcidin. Both CCAAT enhancer binding protein alpha (C/EBP alpha) and interleukin 6 (IL-6) have been shown to regulate hepcidin gene transcription.Aim: To investigate mechanisms underlying alcohol-induced disturbances in iron homeostasis by measuring the expression of hepcidin and C/EBPa mRNA using in vivo and in vitro models of alcoholic liver injury.Methods: Male rats were pair-fed an alcoholic liquid diet for 12 weeks. RT-PCR was performed on liver tissue using specific primers for hepcidin and C/EBP alpha. The effect of alcohol on hepcidin and C/EBP alpha gene expression was also determined in isolated hepatocytes, HuH-7 cells and HepG2 cells treated with 50 mM ethanol, 200 mu M acetaldehyde, and/or 20 ng/ml IL-6.Results: Hepcidin and C/EBPa mRNA expression were significantly decreased in alcohol-fed rats compared with pair-fed controls (6-fold p < 0.001 and 2.2-fold p < 0.0002 reduction, respectively) and hepatic lipid peroxidation was increased by 32.5 % (p < 0.05) in alcohol-fed rats compared with controls. Hepcidin gene expression was not altered significantly in cells cultured in the presence of 50 mM ethanol. Following 24 hour stimulation by IL-6, there was a 4-fold increase in hepcidin expression in hepatocytes and a 9-fold increase in HuH-7 cells. Ethanol (50mM) attenuated the IL-6-induced increase in hepcidin expression in HuH-7 cells (9-fold to a 4-fold increase) but not in hepatocytes. Acetaldehyde had no effect on hepcidin gene expression in cells in culture.Conclusion: The down-regulation of hepcidin and C/EBPa gene expression shown in vivo implies disturbed iron sensing contributing to the hepatosiderosis seen in alcoholic liver disease, possibly by mechanisms involving the IL-6 signaling cascade.