肝细胞核因子1α通过竞争性抑制C/EBPα与NFκB的相互作用从而治疗酒精性肝病的分子机制研究

Alcoholic liver disease （ALD） has been one of the most important liver diseases threatening the health of Chinese people. In previous studies, results showed endotoxin could activate Toll-like receptor 4 (TLR-4) on Kupffer cells in the liver, which then activates NFκB resulting in the imbalance of cytokines. This is one of the important pathogenesis of. The extensive activation of NFκB is dependent on the interaction between C/EBPα and NFκB. In a recent study on the relationship between hepatocyte nuclear factor 1α (hnf1α) and hepatic fibrosis, we found that hnf1α could act on TLR-4 signaling pathway. In terms of the high homology between hnf1α and C/EBPα, we speculate that hnf1α may compete with C/EBPα to bind to NFκB, which then inhibit the interaction between C/EBPα and NFκB. In the present study, the hnf1α expression was down-regulated and up-regulated in rats with ALD, aiming to elucidate the relationship between hnf1α and C/EBPα and to explore the molecular mechanisms underlying the influence of hnf1α on the interaction between C/EBPα and NFκB.

酒精性肝病正日益成为危害我国人民健康最重要的肝病之一。既往国内外的研究发现内毒素激活肝Kupffer细胞表面toll样受体4(TLR4)信号通路从而激活NFκB导致多种细胞因子生成失调引起酒精性肝损伤是酒精性肝病的重要发病机制之一，而NFκB的大量激活依赖于C/EBPα与NFκB的组合效应，最近我们在研究肝细胞核因子1α(hnf1α）与肝纤维化的关系时发现hnf1α可以作用于TLR4信号通路。鉴于hnf1α与C/EBPα之间的高度同源性，故考虑存在肝细胞核因子1α与C/EBPα竞争性的结合NFκB，从而抑制后者与NFκB组合效应的可能。因此本课题拟通过上调和下调hnf1α在酒精性肝病大鼠模型中的表达，初步明确hnf1α与C/EBPα之间的相互关系，从而探讨通过影响C/EBPα与NFκB的组合效应而治疗酒精性肝病的分子机制。