敲除肾素（原）受体阻断脂肪肝发生的关键机制：调节肝脏-脂肪交互对话？

Liver-adipose cross-talking plays an important role in regulating hepatic lipid metabolism. Fibroblast growth factor 21 (FGF21) can promote adiponectin expression in white adipose tissues and increase its plasma levels. Increased adiponectin will increase lipid oxidation and inhibit lipid de novo synthesis in the liver, thus alleviating diet-induced hepatosteatosis. In patients with non-alcoholic fatty liver disease (NAFLD), plasma adiponectin levels were decreased and correlated with the degree of liver steatosis. Recently, we identified the (pro)renin receptor [(P)RR] as a novel regulator of hepatic lipid metabolism. Inhibiting the (P)RR in liver prevents diet-induced obesity and hepatosteatosis. Mechanistic studies revealed that increased fatty acid oxidation and decreased fatty acid synthesis might contribute to the observed phenotype. Yet, we found that diet-induced hepatosteatosis was prevented in liver (P)RR knockout (KO) mice, but not in adipose and liver double KO mice. Worthy to notice, inhibiting the (P)RR in the liver increased hepatic FGF21 expression and plasma levels, and increased adiponectin expression in white adipose tissues. Taken into consideration that liver and adipose (P)RR double KO mice barely had any white adipose tissue, we thus hypothesized that (P)RR reprograms hepatic lipid metabolism via regulation of liver-adipose cross-talking. In this project, we will use adipose transplantation and surgical parabiosis to confirm if hepatic (P)RR deficiency reprograms hepatic lipid metabolism by regulating adipokines secretion. This project, if granted, will increase our understanding of the important roles of liver-adipose cross-talking in hepatic lipid metabolism regulation, and provide theoretic and experimental evidences for developing novel drugs to treat NAFLD.

肝脏-脂肪交互对话对肝脏脂代谢调节十分关键。成纤维细胞生长因子21（FGF21）调节脂肪因子adiponectin的表达。Adiponectin可以增加脂肪酸氧化并抑制脂质合成。在非酒精性脂肪肝患者中，血浆adiponectin下降且和脂肪肝程度密切相关。我们发现敲除肝脏(P)RR能够阻断饮食诱导的脂肪肝，但具体机制未完全明确。肝脏(P)RR减少增加adiponectin转录水平，并增加FGF21血液水平。但在几乎没有白色脂肪的肝脏脂肪(P)RR敲除鼠中，肝脏(P)RR减少并不能阻断脂肪肝。据此我们推测(P)RR可能通过调节肝脏-脂肪交互对话促进脂质氧化并减少脂质合成来阻断脂肪肝发生。我们拟通过脂肪移植和连体手术等经典方法明确(P)RR是否通过影响脂肪因子分泌来调节肝脏脂代谢。开展本项目将阐明(P)RR调节肝脏脂代谢的具体机制，寻找新的调节脂代谢的脂肪因子，为研发脂肪肝防治药物提供新思路。

肝脏-脂肪交互对话对肝脏脂代谢调节十分关键。我们发现敲除肝脏(P)RR能够阻断饮食诱导的脂肪肝，但具体机制未完全明确。肝脏(P)RR减少增加adiponectin转录水平，并增加FGF21血液水平。但在几乎没有白色脂肪的肝脏脂肪(P)RR敲除鼠中，肝脏(P)RR减少并不能阻断脂肪肝。据此我们推测(P)RR可能通过调节肝脏-脂肪交互对话促进脂质氧化并减少脂质合成来阻断脂肪肝发生。本项目探索了肝脏(P)RR是否通过FGF21-adiponectin轴调控肝脏脂代谢，以及肝脏(P)RR是否依赖白色脂肪发挥降低肝脏脂质的作用，以及肝脏(P)RR如何改变脂肪因子的表达及分泌。在此基础上，我们还进一步探索了(P)RR胞外区域，即s(P)RR，敲除后对脂代谢的影响。通过我们的研究，我们明确了肝脏(P)RR不通过FGF21-adiponectin轴调控脂质代谢。但是肝脏(P)RR对肝脏脂质代谢的调控依赖于白色脂肪组织。通过转录组测序以及血液蛋白组分析，我们找到了两个潜在的脂肪因子可能参与了肝脏(P)RR对脂代谢的调控。这一项目的开展明确了肝脏(P)RR通过远端调控脂肪因子分泌改善肝脏脂代谢，相关脂肪因子功能和在体作用的进一步明确降为开发脂肪肝治疗药物提供理论和实验依据。