Oxidized LDL dependent reprogramming of the liver lymphatic endothelium

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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.