Oxidized LDL dependent reprogramming of the liver lymphatic endothelium

肝脏中的淋巴主要来自血管系统，其特征是门静脉和肝动脉在门静脉三联体中横跨肝小叶至中央静脉。来自血管系统的液体通过肝窦内的窗孔渗入肝脏间质。与其他器官的淋巴相比，这些窗孔导致肝淋巴的蛋白质含量更高。在慢性肝病期间，通常在肝脏引流淋巴中发现的高蛋白含量较低。我们观察到饮食诱导的肝病小鼠的淋巴含量也有类似的变化。这种淋巴蛋白含量的变化是否由肝脏淋巴功能缺陷引起，目前尚不清楚。有趣的是，当我们用淋巴生长因子治疗慢性肝病小鼠时，我们能够挽救淋巴引流并减少肝脏的炎症。这些新的发现表明，肝脏中的淋巴管内皮细胞对维持肝脏的动态平衡非常重要。我们还发现，高氧化低密度脂蛋白(OxLDL)注射对淋巴中蛋白质的清除作用与慢性肝病小鼠模型相似。我们发现oxLDL诱导了晶状体上皮细胞转录和代谢谱的显着变化，这表明晶状体上皮细胞的功能发生了变化。此外，我们在体外和体内都发现oxLDL诱导的这些变化依赖于oxLDL受体CD36，这可能是oxLDL导致肝脏淋巴功能障碍的一个潜在机制。在这项提案中，将使用体外和体内模型来i)定义CD36下游导致肝脏淋巴功能障碍的信号通路，以及ii)建立LECs中oxLDL信号导致肝脏淋巴功能降低的分子和细胞后果。这些研究将首次直接解决肝脏中的淋巴管对与肝病相关的炎症介质oxLDL的反应，并可能确定新的治疗靶点，以调节慢性肝病中的淋巴功能。

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.