髓样分化蛋白2介导的脂质堆积和炎症反应在非酒精性脂肪肝中的作用机制研究

Nonalcoholic fatty liver disease (NAFLD) is a chronic inflammatory disease associating with lipid metabolism disorders. To date, the mechanism of NAFLD is still unclear and the clinical treatment is limited, and can’t be completely cured. MD2 is an important protein mediating TLR4’s recognition of LPS. Studies have shown that TLR4’s activation associate with the progression of NAFLD. However, the role of MD2 in NAFLD has not been reported. Our previous study found that oral administration of MD2 small molecule inhibitor L6H21 significantly improved liver lipid accumulation and inflammatory response in a high-fat-induced NAFLD mouse model. Therefore, we propose that MD2 plays an important role in NAFLD, and the inhibition of MD2 attenuate NAFLD. This project will clarify the mechanism of MD2 in the development of NAFLD at the cellular, molecular and animal levels by using small molecule inhibitors, gene silencing and gene knockout mice, elucidate the molecular mechanism that high fat lead to the formation of MD2/TLR4 complex, mediate lipid accumulate through inhibition of PPARγ and mediate inflammatory response through activation of NF-κB, clarify the mechanism of MD2 inhibitor attenuate NAFLD and provide a new target and strategy for the treatment of NAFLD.

非酒精性脂肪肝（NAFLD）是与脂质代谢紊乱相关的慢性炎症性疾病。NAFLD发病机制未明，临床治疗手段有限，尚不能完全治愈。髓样分化蛋白2（MD2）是TLR4识别LPS的重要辅助蛋白。有研究表明TLR4与NAFLD进展相关，但MD2是否在NAFLD发生发展中起作用尚无报道。前期研究发现，在NAFLD小鼠模型中，口服MD2小分子抑制剂 L6H21显著改善高脂饮食诱导的肝脏脂质堆积和炎症反应。因此，我们假设：MD2在NAFLD发生发展中起重要的介导作用，抑制MD2可缓解NAFLD的进程。本项目拟利用小分子抑制剂、基因沉默和转基因小鼠在细胞和动物层面阐明MD2在NAFLD发生发展中的介导作用。阐明高脂通过介导MD2/TLR4复合物形成，抑制下游PPARγ而诱导脂质堆积和激活NF-κB诱发炎症反应的分子机制；明确MD2小分子抑制剂缓解NAFLD的药理作用，为NAFLD的治疗提供新靶点和新策略。

非酒精性脂肪肝（NAFLD）是与脂质代谢紊乱相关的慢性炎症性疾病。NAFLD发病机制未明，临床治疗手段有限，尚不能完全治愈。髓样分化蛋白2（MD2）是TLR4识别LPS的重要辅助蛋白。有研究表明TLR4与NAFLD进展相关，但MD2是否在NAFLD发生发展中起作用尚无报道。本项目采用MD2小分子抑制剂L6H21和MD2基因敲除小鼠阐明了抑制或敲除MD2能够缓解高脂饮食诱导的肝脏脂质堆积、炎症反应和纤维化，并且伴随着肝脏中PPARγ表达的升高；在体内预孵育MD2小分子抑制剂L6H21能够抑制PA诱导的炎症反应以及MD2/TLR4复合物的增加和细胞纤维化。同时，我们发现课题组自主设计合成的新型白藜芦醇-姜黄素杂合物a19在体内可缓解高脂饮食诱导的非酒精性脂肪肝。本项目的实施确证了MD2在NAFLD发生发展过程中的重要介导作用，为NAFLD的治疗提供了新的靶点和候选药物。