CNPY2在有氧运动改善高脂膳食诱导脂肪肝病中的作用及机制研究

It is very important for us to explore the treatment and mechanism of fatty liver diseases. Studies showed that aerobic exercise can effectively improve fatty liver diseases. However, the specific mechanism is still unknown. In our previous study, we found that aerobic exercise can reduce endoplasmic reticulum stress (ERS) and apoptosis induced by non-alcoholic fatty liver diseases. The latest research reported that CNPY2 is involved in ERS and is an important component of ERS pathway. Knockout of CNPY2 can effectively inhibit ERS. Our preliminary results showed that aerobic exercise reduced the protein expression of CNPY2 in the liver of normal rats. Therefore, we speculated that CNPY2 may be a key molecule in aerobic exercise reducing ERS induced by fatty liver diseases. This study proposed from the perspective of CNPY2, based on the foundation of CNPY2 regulating ERS, combined with the knockout rat and cell culture, using Western Blot, RT-PCR, immunofluorescence and immune co-precipitation , in vivo and in vitro, aimed to observe the change of CNPY2 in aerobic exercise improving fatty liver diseases, and clarify the relationship of CNPY2 and ERS in aerobic exercise improving fatty liver diseases, and finally explore the role and mechanism of CNPY2 in aerobic exercise reducing ERS induced by fatty liver diseases.

探究防治和延缓脂肪肝的手段及其机制是摆在我们面前的重要问题。基础研究和实践发现，有氧运动可有效改善脂肪肝，其具体机制不详。我们前期研究发现，有氧运动可降低高脂膳食诱导的非酒精性脂肪肝内质网应激（ERS）、减少细胞凋亡。最新文献报道，CNPY2基因敲除可有效抑制ERS、CNPY2调控ERS信号通路、是ERS通路的重要蛋白组成。课题预实验研究结果显示，有氧运动降低正常大鼠肝脏CNPY2表达。因此推测，CNPY2可能在有氧运动改善脂肪肝ERS中是一个关键分子。本课题拟从CNPY2的视角，以CNPY2调控ERS为出发点，结合基因敲除和细胞培养技术，采用Western Blot、RT-PCR，免疫荧光、免疫共沉淀等检测方法，通过在体动物和离体细胞实验，观察CNPY2在有氧运动改善脂肪肝中的变化，阐明CNPY2与ERS在有氧运动改善脂肪肝中的关系，探讨CNPY2在有氧运动改善脂肪肝ERS中的分子机制。

探究防治和延缓脂肪肝的手段及其机制是摆在我们面前的重要问题。基础研究和实践发现，有氧运动可有效改善脂肪肝，其具体机制不详。本课题通过在体、离体实验，从CNPY2蛋白的角度，结合体内基因敲除术和体外细胞培养术，采用抑制剂、激动剂和重组蛋白，观察CNPY2在有氧运动改善脂肪肝中的变化，阐明CNPY2在有氧运动改善脂肪肝中的作用及其可能机制。本课题研究发现CNPY2介导内质网应激PERK/eIF2a通路参与非酒精性脂肪肝（NAFLD）的形成，高脂膳食诱导NAFLD小鼠肝脏CNPY2-PERK通路相关分子表达升高，有氧运动可有效改善NAFLD，其机制可能与其下调CNPY2表达，抑制PERK/eIF2a通路活性，降低PERK/eIF2a通路相关分子表达，从而抑制肝细胞凋亡、减少肝细胞氧化应激和炎症有关。