瞬时受体电位通道3在高脂膳食诱导的非酒精性脂肪性肝炎中的作用及机制研究

非酒精性脂肪性肝病（NAFLD）是全球流行的慢性肝病。NAFLD包括脂肪肝（NAFL）和脂肪性肝炎（NASH）两个递进阶段，肝细胞损伤是辨别NASH与NAFL的重要指标，抑制肝细胞损伤是阻断NAFL向NASH发展的有效策略。申请人首次发现瞬时受体电位通道3（TRPC3）蛋白表达量在NASH状态下人及小鼠肝脏中显著降低，体外沉默TRPC3可显著诱导肝细胞损伤，过表达TRPC3可显著改善氧化应激、脂毒性等致NASH风险因素诱导的肝细胞损伤。然而TRPC3表达减少能否导致NASH发生；逆转TRPC3减少能否改善NASH；TRPC3如何调控肝细胞损伤及NASH进程等科学问题有待深入研究。本项目拟通过揭示上述科学问题系统阐述TRPC3在高脂膳食诱导的肝细胞损伤及NASH中的作用及分子机制。项目的顺利实施对揭示NASH防控的分子靶点、药物研发、降低我国NASH发病率具有重要的理论意义和潜在的临床价值。

Non-alcoholic fatty liver disease (NAFLD) is a global epidemic chronic liver disease. Non-alcoholic fatty liver disease (NAFL) and non-alcoholic steatohepatitis (NASH) are two stages of NAFLD development. Since hepatocyte injury is an important index for judgment of NASH and NAFL, inhibiting hepatocytes injury is an effective strategy to block the development from NAFL to NASH and improve NAFLD. For the first time, the applicant found that the hepatic protein expression of transient receptor potential channel 3 (TRPC3) was significantly reduced in human and mice under NASH condition. Besides, in vitro study revealed that silencing TRPC3 can significantly induce hepatocytes injury; Overexpression of TRPC3 can significantly improve hepatocytes injury-induced by NASH risk factors such as oxidative stress and lipotoxicity. However, whether the decrease of TRPC3 expression can lead to NASH, can reversing TRPC3 downregulation improve NASH, and how TRPC3 regulates hepatocytes injury and NASH processes remain to be studied in depth. This project aims to systematically elaborate the role and molecular mechanism of TRPC3 in hepatocytes injury and NASH induced by high-fat diet by revealing the above scientific problems. The successful implementation of the project has important theoretical significance and potential clinical value for revealing the molecular targets of NASH prevention and control, drug research and development, and reducing the incidence of NASH in China.