Oxidized LDL dependent reprogramming of the liver lymphatic endothelium

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合一中跨越肝小叶到中央静脉。从血管中流出的液体通过肝窦的小孔渗漏到肝间质。与其他器官的淋巴相比，这些空隙导致肝淋巴中蛋白质含量更高。在慢性肝病中，通常在肝脏引流淋巴中发现的高蛋白含量较低。我们观察到饮食性肝病小鼠的淋巴含量也发生了类似的变化。这种淋巴蛋白含量的改变是否由于肝脏淋巴功能的缺陷尚不清楚。有趣的是，当我们用淋巴生长因子治疗患有慢性肝病的小鼠时，我们能够挽救淋巴排水并减少肝脏炎症。这些新发现表明，肝脏淋巴内皮在维持肝脏稳态中起重要作用。我们还发现，高度氧化的低密度脂蛋白（oxLDL）注射对慢性肝病小鼠模型的淋巴蛋白清除具有相似的效果。我们发现，oxLDL诱导了LECs转录和代谢谱的显著变化，这表明LECs的功能发生了变化。此外，我们发现这些oxLDL诱导的变化在体外和体内都依赖于oxLDL受体CD36，这表明oxLDL诱导肝淋巴功能障碍的潜在机制。在本提案中，将使用体外和体内模型来i)定义驱动肝脏淋巴功能障碍的CD36下游信号通路，ii)确定导致肝脏淋巴功能下降的LECs中oxLDL信号的分子和细胞后果。这些研究将首次直接探讨肝脏淋巴系统如何对与肝脏疾病相关的炎症介质oxLDL做出反应，并有可能确定慢性肝病中调节淋巴功能的新治疗靶点。

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 i) define the signaling pathway downstream of CD36 that drives lymphatic dysfunction in the liver and ii) 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.