Oxidized LDL dependent reprogramming of the liver lymphatic endothelium

项目摘要 肝脏中的淋巴主要来源于血管系统，其特征是 门静脉和肝动脉在门静脉三联体中横跨肝小叶和中央静脉。液体来自于 血管通过肝窦内的窗孔渗入肝脏间质。这些隔板 与其他器官的淋巴相比，肝淋巴的蛋白质含量较高。高蛋白 在慢性肝病期间，通常在肝脏引流淋巴中发现的含量较低。我们观察到类似的情况 饮食性肝病小鼠淋巴含量的变化。如果淋巴蛋白含量的这种变化是 由于肝脏淋巴功能缺陷，目前尚不清楚。有趣的是，当我们治疗患有慢性肝病的小鼠时 有了淋巴生长因子，我们就能够挽救淋巴引流，减少肝脏的炎症。 这些新的发现表明，肝脏中的淋巴管内皮细胞对维持肝脏非常重要 动态平衡。我们还发现，高氧化低密度脂蛋白(OxLDL)注射也有类似的作用 淋巴蛋白质清除作为慢性肝病小鼠模型。我们发现oxLDL可以诱导 晶状体上皮细胞转录和代谢谱的显著变化表明 LECs。此外，我们发现这些oxLDL诱导的改变依赖于oxLDL受体。 CD36在体外和体内的表达，提示oxLDL诱导肝脏淋巴循环的可能机制 功能障碍。在这项提案中将使用体外和体内模型来建立分子和细胞 氧化低密度脂蛋白信号在LECs中导致肝脏淋巴功能下降的后果。这些研究将是 第一个直接研究肝脏中的淋巴管如何对与肝脏相关的炎症介质作出反应的论文 疾病，oxLDL，并可能确定新的治疗靶点，以调节淋巴功能的环境 慢性肝病。

Project Summary The lymph in the liver originates predominantly from the blood vascular system, which is characterized by a portal vein and hepatic artery in the portal triad spanning the hepatic lobule to the central vein. Fluid from the blood vasculature leaks into the interstitium of the liver through fenestrae in liver sinusoids. These fenestrae result in a higher protein content of hepatic lymph as compared to lymph in other organs. The high protein content normally found in the liver draining lymph is lower during chronic liver disease. We observe similar changes in lymph content in mice with diet-induced liver disease. If this alteration in lymph protein content is due to defective liver lymphatic function is unknown. Intriguingly, when we treat mice with chronic liver disease with a lymphatic growth factor we are able to rescue lymphatic drainage and decrease inflammation in the liver. These novel findings demonstrate that the lymphatic endothelium in the liver important for maintaining liver homeostasis. We also find that highly oxidized low-density lipoprotein (oxLDL) injection has a similar effect on lymphatic removal of protein as a mouse model of chronic liver disease. We discovered that oxLDL induced significant changes in the transcriptional and metabolic profile of LECs which indicate a functional change in LECs. Furthermore, we found that these oxLDL-induced changes were dependent on the oxLDL receptor CD36 both in vitro and in vivo, suggesting a potential mechanism by which oxLDL induces liver lymphatic dysfunction. In this proposal will use both in vitro and in vivo models to establish the molecular and cellular consequences of oxLDL signaling in LECs that cause decreased liver lymphatic function. These studies will be the first to directly address how lymphatics in the liver react to an inflammatory mediator associated with liver disease, oxLDL, and potentially identify novel therapeutic targets to modulate lymphatic function in the setting of chronic liver disease.