TAK1在TLR4介导的肝星状细胞活化中的作用及机制

Hepatic stellate cell(HSC) activation is the key to trigger liver fibrogenesis through production and deposition of extracellular matrix (ECM). The damage associated molecular patterns (DAMPs) released from injured organs and a large amount of bacteria translocated to the liver can activate HSCs through activation of TLR4 signaling. TAK1(TGF-β-activated kinase1) is a key component in TLR4 signaling. Our previous study found that TAK1 plays a crucial role in hepatocytes in regulation of cell death and proliferation, but its role in HSCs is still unknown. In this study we will specifically investigate the role of TAK1 in TLR4 signaling in HSCs. We will examine if TAK1 is required for forming the TLR4-signaling complex in HSCs. And we will also explore if TAK1 regulates HSC activation by down-regulating Bambi gene expression. We will further evaluate whether specific deletion of TAK1 in hepatic stellate cells can suppress liver fibrosis induce by CCl4 or BDL in vivo. Our study will further clarify the critical role and mechanism of TAK1 on HSCs activation and liver fibosis.We wish to provide new therapeutic target for liver fibrosis.

肝星状细胞（hepatic stellate cells，HSCs）活化，并向成纤维细胞转化、分泌大量细胞外基质及细胞因子，是肝纤维化形成的核心环节。各类损伤相关的病原分子及来自肠道移位的病原微生物，可激活TLR4诱导HSCs 活化。TAK1是TLR4信号途径中的重要分子，前期研究发现TAK1在调控肝细胞凋亡及增殖中发挥重要作用，而在HSCs中的作用尚不明确。本课题通过体外实验明确在HSCs活化过程中TAK1是否为TLR4信号途径的必需分子，TAK1是否通过调控Bambi的表达促进HSCs活化；并通过体内实验在小鼠HSCs中敲除TAK1，观察对CCL4及BDL诱导的肝纤维化及HSCs活化的影响。本课题可以进一步明确TLR4信号诱导HSCs活化的作用机制，而且可以更深入了解TAK1在肝纤维化及HSCs活化中的作用，并为肝纤维化的治疗提供靶点。

本项目发现TLR4/MyD88是肝星状细胞活化产生细胞因子的关键途径，TAK1活化是HSCs在LPS刺激后形成TLR4信号复合体形成的早期事件，TLR4通过MyD88 而不是TRIF下调Bambi的表达；TLR4的下游信号分子MyD88是NASH与纤维化进展的关键衔接蛋分子；TRIF为肝脏炎症与纤维化的新型调节因子；TLR4与TLR9通过TNFR促进肝细胞特异敲除TAK1的小鼠肝脏炎症、纤维化与癌变。并首次发现肝细胞内TAK1的上游分子TGFβR2通过促进脂变肝细胞死亡及抑制脂质β氧化代谢参与NASH发生；肝细胞内的TAK1通过AMPK/mTORC1轴介导自噬及脂肪酸氧化，阻止肝脏脂肪变性及肿瘤的发生发展。此项研究为肝脏脂变、炎症、纤维化及癌变的防治提供了治疗靶点与实验依据。该项目在Hepatology、J Clinical Investigation、 Int J Cancer、Cancer Letters等杂志发表SCI论文7篇，被Nature、Cell、Cell Metabolism、Hepatology等一流国际期刊他引90余次，并培养硕士研究生4名，博士研究生3名，同时项目组成员共获得国家自然科学基金项目4项。