14-3-3β对非酒精性脂肪肝脂质沉积的影响及分子机制研究

Non-alcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis is the major cause of chronic liver disease. Glucagon could regulate liver lipid metabolism through glucagon receptor (GCGR). Our previous research screened 14-3-3β as a GCGR binding protein, and first found that it could ameliorate gluconeogenesis in hepatocytes by combining with GCGR. However, it is still unclear whether it is involved in the lipid metabolism. Preliminary experiments from our group revealed that 14-3-3β combined with GCGR can affect the expression of key enzymes of lipid synthesis, but the mechanism is not clear. Therefore, our study is aimed to (1) clarify the effect and molecular mechanism of 14-3-3β on GCGR regulating lipid metabolism by the hepatocyte model of 14-3-3β overexpression/ knockdown; (2) observe the changes of lipid metabolism phenotypes in liver specific 14-3-3β knockout and overexpression mouse model. The result of the study explore the effect and mechanism of 14-3-3β on liver lipid deposition through the perspective of molecular, cell and animal ,which will illuminate novel strategy of preventing and controlling NAFLD.

非酒精性脂肪肝（NAFLD）以肝脏脂质沉积为病理特征，是导致慢性肝脏疾病的主要病因。胰高血糖素可通过结合胰高血糖素受体（GCGR）调节肝脏脂代谢。本课题组前期筛选出GCGR结合蛋白14-3-3β，首次发现其协同胰高血糖素可抑制肝细胞糖异生，但其能否影响脂代谢尚不清楚。前期研究证实，14-3-3β协同胰高血糖素可影响脂质合成关键酶的表达，但机制不明。为此，本研究将：（1）利用过表达/沉默14-3-3β肝细胞模型，探讨其协同胰高血糖素对脂代谢的影响及分子机制；（2）采用肝脏特异性14-3-3β敲除小鼠和过表达小鼠模型，观察不同条件下动物肝脏脂质代谢表型变化，从分子、细胞及动物整体水平探讨14-3-3β影响肝脏脂质沉积的详细机制，为NAFLD的防治提供新的思路。

非酒精性脂肪肝（NAFLD）以肝脏脂质沉积为病理特征，是导致慢性肝脏疾病的主要病因。目前 NAFLD 的治疗主要包括生活方式干预、药物治疗以及代谢手术。治疗药物，如胰岛素增敏剂、降脂药物虽然可以在一定程度上改善脂肪变性，但存在增加体重、促进纤维化进展等各种副作用。因此，临床上急需开发新的药物治疗NAFLD。胰高血糖素是胰岛 α 细胞分泌的一种肽类激素，可通过结合胰高血糖素受体（GCGR）调节肝脏脂代谢。因而，调节 GCGR 信号通路可能成为脂肪性肝病新的治疗手段。本课题组前期筛选出GCGR结合蛋白14-3-3β，首次发现其可抑制胰高血糖素诱导的肝细胞糖异生，但其能否影响脂代谢尚不清楚。本研究发现，通过腺病毒特异性过表达肝脏中的YWHAB可减少高脂诱导的NAFLD小鼠肝脏中脂质沉积；同样，YWHAB 肝脏特异性敲除可增加普食及GAN诱导的NAFLD小鼠肝脏脂质沉积。此外，通过转录组及蛋白组分析YWHAB 肝脏特异性敲除小鼠及对照小鼠肝脏组织发现，YWHAB可能是通过SCD1影响脂代谢过程。本研究为寻找新的治疗NAFLD药物提供了线索，同时也为更进一步阐明NAFLD的发病机制提供新的理论，为NAFLD的防治提供新的思路。