转录因子EB介导成纤维细胞生长因子21缓解非酒精性脂肪肝的机制研究

The mechanism of nonalcoholic fatty liver disease (NAFLD) is not clear till now, with poor therapeutic effects. Transcription factor EB (TFEB), an important regulatory protein in disorders of lipid metabolism, belongs to basic helix-loop-helix leucine zipper family members. Our previous studies demonstrated that the lipid accumulated more in the TFEB liver-specific knock out (TFEB LKO) mice than in wild-type (WT) mice when fed with high fat diet induced nonalcoholic fatty liver disease, and serum TG and TC levels increased dramatically in TFEB LKO mice, however, the underlying mechanism are still unclear. On the basis of these previous findings, our study aim to further investigate the potential protective effects of TFEB in NAFLD through the methods of “gain of function” and “loss of function” by using TFEB LKO mice and TFEB overexpressed mice. Furthermore, we also found TFEB can up-regulate fibroblast growth factor 21 (FGF21) expression level by activating FGF21’s promoter activity, and we will further discuss the regulatory mechanism and effects of TFEB in the NAFLD, which will provide a novel basis for searching new drug target of treating NAFLD.

非酒精性脂肪肝的发病机制尚不清楚，治疗效果欠佳，转录因子EB（TFEB）是碱性亮氨酸拉链家族（bHLH-Zip）成员之一，是参与机体脂质代谢过程的重要转录调控蛋白，我们的前期研究结果发现，在饮食诱导小鼠非酒精性脂肪肝模型中，与对照野生型小鼠相比，TFEB肝脏特异性敲除小鼠（TFEB LKO）肝脏脂肪沉积程度显著增加，血清总胆固醇（TC）、甘油三酯（TG）水平明显增高，而具体机制未明。我们还发现，TFEB能够激活成纤维细胞生长因子21（FGF21）上游启动子活性并调控FGF21的转录，因此本项目拟以此为基础，采用腺病毒载体过表达TFEB和TFEB LKO小鼠为研究对象，通过“功能获得”和“功能缺失”的方法探讨TFEB对非酒精性脂肪肝的作用及其分子机制，提高对非酒精性脂肪肝发病机制的认识，为非酒精性脂肪肝的治疗提供新的理论基础及治疗靶点。

非酒精性脂肪肝（NAFLD）的发病机制尚不清楚，治疗效果欠佳，转录因子EB（TFEB）是碱性亮氨酸拉链家族（bHLH-Zip）成员之一，是参与机体脂质代谢过程中的重要转录调控蛋白。在本项目中，我们观察了喂食、禁食以及重喂食后引起的生理性能量缺失状态下及高脂饮食喂养的病理状态下脂肪肝小鼠中TFEB的表达。同时，我们采用TFEB干扰腺病毒及过表达腺病毒处理NAFLD小鼠，从而在“功能获得”及“功能缺失”条件下观察TFEB对NAFLD小鼠的作用。我们发现，TFEB能够通过作用FGF21启动子来调控FGF21的表达及分泌，然而TFEB对NAFLD的具体作用还有待阐明，因此本项目将为NAFLD的治疗提供新的药物靶点及理论依据。