肝脏蛋白质异戊二烯化介导特异性因子分泌以调控脂肪组织功能的研究

The liver plays a central role in systemic glucose and lipid metabolism by releasing specific hepatokine. Specially, liver significantly influences adipose tissue's function. Under metabolic disorder, like high fat-diet induced non-alcoholic fatty liver disease (NAFLD), the mechanism of liver-derived secretory factors to regulate adipose tissue's function is unclear. Our results have shown that the expression of Geranylgeranyldiphosphate synthase (GGPPS) in the liver was highly increased in obesity-associated NAFLD models and GGPPS influenced hepatic lipid metabolism. Meanwhile, the hepatic metabolic disorder leads to the changes of white adipose tissue's function. In this project, we will combine in vivo and in vitro models to find out the liver-derived secretory factors which regulates adipose tissue's function under NAFLD, unraveling the function and molecular mechanisms of liver-derived secretory factors regulated by protein prenylation in liver. This study intends to throw a light on metabolic homeostasis regulated by liver.

肝脏是重要的代谢器官，可以通过释放特定因子调控机体的糖脂代谢，特别是脂肪组织功能。但在代谢异常情况下，如高脂食物导致非酒精性脂肪肝时，肝脏释放特异性分泌因子继而导致脂肪组织功能异常的分子机制尚不明确。我们的动物实验表明，高脂食物可导致肝脏香叶基香叶基焦磷酸合成酶（Geranylgeranyldiphosphatesynthase,GGPPS)的升高，并通过调节肝脏中蛋白质异戊二烯化状态影响肝脏的脂质积累；同时肝脏的代谢异常也会引起白色脂肪组织功能的改变。本项目拟通过体内和体外实验研究在非酒精性脂肪肝情况下，肝细胞通过蛋白质异戊二烯化调控肝脏特异性因子分泌的作用方式和分子机制，以及这些肝细胞分泌因子对脂肪组织功能的影响，为了解肝脏如何调控机体代谢平衡提供了一个新的角度。

本研究从人群、动物、细胞和分子水平探究了在不同代谢压力下（短时或长时高脂喂养），肝细胞分泌影响脂肪组织发挥功能的特异性因子-细胞外囊泡（EV），明确了肝脏通过GGPPS调节Rab蛋白异戊二烯化介导肝脏EV分泌的作用方式，并利用肝脏特异性敲除GGPPS的小鼠模型，结合临床脂肪肝（NAFLD）样本，运用miRNA芯片筛选等技术明确了肝脏EV-miRNA调控脂肪组织脂质积累的机制，不仅建立了肝脏响应代谢状态改变从而远端调控脂肪组织的模型，同时也开发了一种提纯肝脏EV的新方法—超速离心结合密度梯度离心，为研究肝脏如何调控机体代谢平衡提供了一个新的理论模型及技术方法。