TIPE1感知脂肪酸信号、调控mTORC2通路抑制NAFLD的作用及机制研究

NAFLD是最常见的肝脏慢性疾病，严重危害人类健康。目前尚缺乏有效干预手段。TIPE1分子是由本课题组鉴定的新抑癌基因，具有潜在脂质结合能力。前期研究发现，脂肪变肝细胞中TIPE1表达下调，敲除/干扰TIPE1表达影响脂代谢途径、加重肝脂质沉积；TIPE1能够结合脂肪酸，并被脂肪酸诱导与mTORC2互作、调控其活化，而干预mTORC2则逆转TIPE1对肝脂质沉积的影响。据此，提出本课题假说：TIPE1感知脂肪酸、调控mTORC2维持肝脂代谢稳态、抑制NAFLD进程。本课题拟利用基因敲除小鼠、慢病毒感染结合突变体分析等技术，通过体内外实验和临床检测，明确TIPE1对肝脂代谢和NAFLD发生发展的影响，确定TIPE1的脂肪酸结合活性，并探讨mTORC2通路参与TIPE1感知脂肪酸调控肝脂代谢的机制。研究的实施将有助于揭示TIPE1分子的新型生物学功能和作用网络，为NAFLD干预治疗提供新靶点

Non-alcoholic fatty-liver disease, the most common chronic liver disease, seriously affect human being’s health. Till now, there is no any efficient therapy for NAFLD. TIPE1, a novel tumor-suppressor gene identified by our group, has the potential ability to bind with lipids. We previously found that TIPE1 expression was decreased in fatty liver and TIPE1 knockdown or interference aggravated hepatocyte steatosis. In addition, SPR analysis and immunoprecipiation-mass spectrometry showed the binding of TIPE1 with OA, which then stimulated the interaction of TIPE1 with mTORC2 and regulated its activation. More importantly, mTORC2 interference reversed the effects of TIPE1 on lipid accumulation. Thus, we hypothesize that TIPE may function as a sensor of fatty acid and maintains lipid homeostasis and inhibit NAFLD development by regulating mTORC2 signaling pathway. By using mutant analysis, SPR assay and functional blockade design, this project aims to clarify the roles of TIPE1 in hepatocyte steatosis and NAFLD progression, and to explain the molecular mechanisms of TIPE1 regulation on hepatocyte lipid metabolism by sensing fatty acids and regulating mTORC2 pathway. This study would be helpful for unraveling the novel biological functions and molecular network of TIPE1 and provide new targets for clinical therapy of NAFLD.