Injury-induced changes in liver specific transcription factors HNF-1α and HNF-4α.
Injury-induced changes in liver specific transcription factors HNF-1α and HNF-4α.
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损伤引起的肝脏特异性转录因子 HNF-1α 和 HNF-4α 的变化。
DOI：
10.1016/j.jss.2011.04.062
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Burke,PeterA
中科院分区：
文献类型：
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作者：
Bauzá,Graciela;Miller,Glenn;Kaseje,Neema;Wang,Zhongyan;Sherburne,Alan;Agarwal,Suresh;Burke,PeterA
肝脏急性期反应（APR）是一种对多种损伤的器官特异性反应，在很大程度上受转录控制。肝脏特异性转录因子肝核因子（hepatic nuclear factors，HNF）-1α和4α在维持肝脏表型和功能中起重要作用，其结合活性在损伤后早期发生变化。材料和方法将SC 57/BL 6小鼠麻醉并暴露于95 ℃水中10秒，以产生15%体表面积的全层烧伤。在特定时间点，处死小鼠。采用ELISA法检测血清和肝脏中IL-6、纤维蛋白原-γ和血清淀粉样蛋白A（SAA）-3的mRNA水平。血清IL-6水平在3 h达到峰值，纤维蛋白原-γ和SAA mRNA水平在12 h增加6倍以上，48 h恢复到对照水平。HNF-4α和HNF-1α的结合活性在伤后1.5h迅速下降，但分别在24和6 h恢复到接近对照水平。结论HNF-4α和HNF-1α结合活性的变化发生在急性期蛋白mRNA水平变化之前，并在IL-6水平达到峰值之前。损伤后肝脏特异性转录因子结合的快速抑制和重建可能代表了一种机制，该机制允许正常肝脏表型改变和损伤反应表型占上风。肝脏对损伤的适应性反应中的这种机制表明HNF-4α和HNF-1α在肝脏APR的转录调节中起核心作用。
BACKGROUNDThe hepatic acute phase response(APR) is an organ-specific response to a diverse array of insults and is largely under transcriptional control. Liver-specific transcription factors, hepatic nuclear factors (HNFs)-1α and 4α play important roles in maintenance of liver phenotype and function and their binding activity changes early after injury. However, their roles in modulation of the liver’s response over time are not defined.MATERIALS AND METHODSC57/BL6 mice were anesthetized and exposed to 95°C water for 10 s to create a 15% body surface area full-thickness burn. At specific time points, the mice were sacrificed. An ELISA for IL-6 was performed on serum and hepatic mRNA levels for fibrinogen-γ and serum amyloid A(SAA)-3 were obtained through polymerase chain reaction (PCR). Transcriptional factor binding activity was assessed with electrophoretic mobility shift assays.RESULTSSerum IL-6 levels peaked at 3 h and fibrinogen-γ and SAA mRNA levels increased more than 6-fold at 12 h before returning to control levels at 48 h. The binding activity of HNF-4α and HNF-1α rapidly declined after injury (1.5 h) but recovered to near control level at 24 and 6 h, respectively.CONCLUSIONSChanges in HNF-4α and HNF-1α binding occurred before changes in acute phase protein mRNA levels and were preceded by the peak in IL-6 levels. The rapid suppression and reconstitution of liver-specific transcription factor binding after injury may represent a mechanism that allows the normal liver phenotype to change and an injury-response phenotype to prevail. This mechanism in the liver’s adaptive response to injury suggests a central role for both HNF-4α and HNF-1α in transcriptional regulation of the hepatic APR.