MRTF-A通过调控Wnt/b-catenin信号通路参与肝脏再生的机制研究

A host of pathogenic factors induce liver injury leading to necrosis of hepatocyte. Liver regeneration can compensate for the loss of liver parenchyma and maintain normal liver function. On the contrary, dysfunction of liver regeneration results in liver failure and consequently deaths of patients. The Wnt/b-catenin signaling pathway plays a pivotal role in regulating liver regeneration. The underlying mechanism, however, remains to be completely sorted out. Our preliminary data suggest that the transcriptional modulator MRTF-A interacts with b-catenin and enhances b-catenin stability. MRTF-A deficiency or MRTF-A inhibition results in dampened transcriptional activity of b-catenin. Importantly, a specific MRTF-A inhibitor attenuates liver regeneration following APAP-induced liver injury. Of interest, MRTF-A also contributes to the transcription of several Wnt ligand genes in macrophages. These data collectively suggest that on the one hand, MRTF-A enhances the activity of b-catenin in hepatocytes and on the other hand promotes the production of Wnt ligands in macrophages. Based on this hypothesis, we plan to further investigate the mechanism whereby MRTF-A regulates the Wnt/b-catenin signaling pathway and by extension liver regeneration.

多种因素导致肝损伤引起肝细胞坏死。肝细胞再生可以代偿失去的肝实质，维持其正常功能；相反，肝细胞再生障碍则导致肝功能衰竭。Wnt/b-catenin信号通路是肝细胞再生中的重要环节，但其中的调控机制并未完全阐明。我们的预实验结果证实，转录因子MRTF-A与b-catenin互相作用并增强b-catenin蛋白质稳定性。MRTF-A缺陷或活性抑制削弱b-catenin转录活性。MRTF-A抑制剂在小鼠中显著抑制APAP诱导急性肝损伤后的肝脏再生。有意思的是，MRTF-A在巨噬细胞中调控多种Wnt配体的表达。以上结果提示，MRTF-A可能一方面在肝细胞中增强b-catenin转录活性，另一方面在巨噬细胞中促进Wnt配体的表达，从而促进肝脏再生。基于这一假说，我们拟进一步深入探讨MRTF-A调控Wnt/b-catenin信号通路促进肝脏再生的机制，以期为临床治疗肝损伤提供理论依据和药物靶标。

多种因素导致肝损伤引起肝细胞坏死。肝细胞再生可以代偿失去的肝实质，维持其正常功能；相反，肝细胞再生障碍则导致肝功能衰竭，但其中的转录机制尚未完全阐明。在项目实施的三年中，我们围绕转录因子MRTF-A及其辅因子BRG1调控肝脏损伤和修复的表观遗传学机制进行了系统性研究。主要发现有（1）MRTF-A、BRG1、CEBP形成一个转录复合物共同调控肝细胞中CRP转录激活，从而促进肝脏炎症应激和脂肪性损伤。（2）MRTF-A和转录因子SRF协同招募组蛋白甲基转移酶及组蛋白乙酰转移酶共同促进肝星状细胞激活，从而诱导肝脏损伤和肝纤维化。（3）MRTF-A通过激活TWIST1转录，诱导肝窦内皮细胞发生间质性转化，从而促进肝纤维化。（4）BRG1通过和SREBP2互相作用招募组蛋白去甲基酶促进肝细胞中胆固醇合成，从而肝脏脂肪性损伤。（5）MRTF-A通过激活USP47转录稳定b-catenin和YAP从而促进肝细胞增殖和肝脏再生。因此，我们的结果指出了肝脏损伤和修复相关转录新的调控机制，并且为临床干预肝损伤和促进肝脏修复提供了思路。上述部分成果已经在BBA-Gene Regul Mech、Front Cell Dev Biol、J Mol Med、Redox Biol等国际期刊发表研究论著共计7篇，其余成果目前正在整理投稿过程中。