Cholestasis downregulate hepcidin expression through inhibiting IL-6-induced phosphorylation of signal transducer and activator of transcription 3 signaling
Cholestasis downregulate hepcidin expression through inhibiting IL-6-induced phosphorylation of signal transducer and activator of transcription 3 signaling
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DOI：
10.1038/labinvest.2009.82
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发表时间：
2009-10-01
影响因子：
5
通讯作者：
Chen, Chao-Long
中科院分区：
文献类型：
--
作者：
Huang, Ying-Hsien;Chuang, Jiin-Haur;Chen, Chao-Long
肝调素在胆道闭锁的进行性胆汁淤积过程中下调，但其机制尚不清楚。为了验证hepcidin的下调是否特异于胆汁淤积而与患者的年龄无关，我们首先分析了原发性胆汁性肝硬化（PBC）（n = 4）、非胆汁淤积性肝硬化（n = 9）和对照（n = 9）成人中的肝hepcidin mRNA和蛋白质表达。我们评估了酪氨酸磷酸化的信号转导和转录激活因子3（pSTAT 3）的表达在肝脏切片。本研究通过结扎肝外胆管（BDL）建立大鼠胆汁淤积模型，并在BDL后2周建立脂多糖（LPS）诱导的胆汁淤积大鼠胆管炎模型，采用实时定量逆转录-PCR、免疫组化、RT-PCR蛋白质印迹和酶联免疫吸附测定（ELISA）。进行胆汁酸对铁调素表达的影响的体外研究以再次确认体内发现。与非胆汁淤积性肝硬化相比，胆汁淤积性肝硬化中hepcidin mRNA和pSTAT 3蛋白表达显著降低。BDL组hepcidin和gp 130 mRNA表达较假手术组和正常对照组明显降低。此外，在患者和BDL大鼠的胆汁淤积性肝脏中，pSTAT 3蛋白表达和核转位显著降低，这与较低的肝脏hepcidin mRNA和血浆hepcidin表达相当。此外，BDL 2周减弱LPS诱导的hepcidin表达上调。疏水性胆汁酸甘氨鹅脱氧胆酸盐抑制IL-6诱导的原代肝细胞pSTAT 3表达，并导致hepcidin mRNA表达下调。综上所述，胆汁淤积或其重要成分--疏水性胆汁酸可通过抑制IL-6诱导的STAT 3磷酸化和pSTAT 3蛋白核转位下调hepcidin的表达。实验室调查（2009）89，1128-1139; doi：10.1038/labinvest.2009.82; 2009年8月3日在线发表
Hepcidin is downregulated during progressive cholestasis in biliary atresia, but the mechanism is unknown. To verify whether downregulation of hepcidin is specific to cholestasis irrespective of the patient's age, we first analyzed liver hepcidin mRNA and protein expression in adults with primary biliary cirrhosis (PBC) (n = 4), non-cholestatic cirrhosis (n = 9) and in controls (n = 9). We evaluated the tyrosine phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) expressions in the liver sections. A rat model of cholestasis by ligation of the extrahepatic bile duct (BDL) was created, and lipopolysaccharide (LPS)-induced cholangitis in cholestatic rats 2 weeks after BDL was also established to study the modulation of hepcidin by interleukin-6 (IL-6) and STAT3 signaling pathway in these models, using real-time quantitative reverse transcription-PCR, immunohistochemistry, western blotting and enzyme-linked immunosorbent assay (ELISA). An in vitro study of the effect of bile acids on hepcidin expression was carried out to re-confirm the in vivo findings. There was significantly lower hepcidin mRNA and pSTAT3 protein expression in cholestatic cirrhosis compared with non-cholestatic cirrhosis in adults. BDL caused significant decrease in hepcidin and gp130 mRNA expression compared with sham-operated group and normal control. Furthermore, there was significantly lower pSTAT3 protein expression and nuclear translocation in the cholestatic liver from the patients and the BDL rats, which was comparable to lower liver hepcidin mRNA and plasma hepcidin expression. Furthermore, BDL for 2 weeks attenuated the upregulation of hepcidin expression induced by LPS. Hydrophobic bile acid glycochenodeoxycholate inhibited IL-6-induced pSTAT3 expression in primary hepatocytes and resulted in the downregulation of hepcidin mRNA expression. In conclusion, the study shows that cholestasis or its important component-hydrophobic bile acids-can downregulate hepcidin expression through inhibiting IL-6-induced STAT3 phosphorylation and pSTAT3 protein nuclear translocation. Laboratory Investigation (2009) 89, 1128-1139; doi:10.1038/labinvest.2009.82; published online 3 August 2009