ROLE OF LYMPHATIC VESSELS IN CHOLESTEROL CLEARANCE AND THE INVOLVEMENT OF HIGH DENSITY LIPOPROTEINS IN REGULATING LYMPHATIC FUNCTION

Abstract

Despite the emerging link between cholesterol and lymphatic function, the mechanisms controlling this interplay in health and disease have been poorly explored. The removal of cholesterol with high-density lipoproteins (HDLs) as carriers, from the peripheral tissues to the bloodstream and finally into the liver for subsequent excretion in the bile and feces also known as reverse cholesterol transport (RCT), is a process of major biological importance. In this study, we demonstrated that lymphatic drainage is critical for RCT as surgical obstruction of lymphatic vessels in wild-type mice significantly impaired RCT. We have previously shown that hypercholesterolemia in mice is associated with impaired lymphatic drainage and increased lipid accumulation in peripheral tissues. We now show that restoring lymphatic drainage in these mice significantly improved cholesterol clearance and promoted RCT. Finally, we demonstrated that HDL may not only mediate cholesterol clearance via the lymphatic vessels but also regulate the lymphatic vasculature at homeostasis. Notably, we found in mice that low HDL levels or dysfunctional HDL were associated with compromised lymphatic drainage in hypercholesterolemic and SR-BI deficient mice, respectively. Conversely, the treatment of hypercholesterolemic mice with HDL alone was sufficient to improve lymphatic drainage. The beneficial effect of HDL on lymphatic transport was in part, associated with the regulation of vascular endothelial growth factor C (VEGF-C) by macrophages, a growth factor crucial for the integrity and function of the lymphatic vasculature. Altogether, this study demonstrated the interplay between lymphatic function and lipid biology and also provides critical insights on novel function of HDL in regulating lymphatic drainage. Such knowledge will lead to more efficacious treatments and the identification of potential new therapeutic targets for treating lipid and/or lymphatic related lymphatic diseases.