The role of the lymphatic system in cholesterol transport

Abstract

Reverse cholesterol transport (RCT) is the pathway for removal of peripheral tissue cholesterol and involves transport of cholesterol back to liver for excretion, starting from cellular cholesterol efflux facilitated by lipid-free apolipoprotein A1 (ApoA1) or other lipidated high-density lipoprotein (HDL) particles within the interstitial space. Extracellular cholesterol then is picked up and transported through the lymphatic vasculature before entering into bloodstream. There is increasing evidence supporting a role for enhanced macrophage cholesterol efflux and RCT in ameliorating atherosclerosis, and recent data suggest that these processes may serve as better diagnostic biomarkers than plasma HDL levels. Hence, it is important to better understand the processes governing ApoA1 and HDL influx into peripheral tissues from the bloodstream, modification and facilitation of cellular cholesterol removal within the interstitial space, and transport through the lymphatic vasculature. New findings will complement therapeutic strategies for the treatment of atherosclerotic vascular disease.

Keywords: apolipoprotein A1; atherosclerosis; cholesterol efflux; cholesterol reverse transport; high-density lipoprotein modification; high-density lipoprotein transport; interstitial space; lymphatics.

FIGURE 1

Forward and reverse cholesterol transport. The forward cholesterol transport starts from the liver, which generates triglyceride-rich verylow-density lipoprotein (VLDL) and releases it into circulation. VLDL is progressively hydrolyzed and forms intermediate and low-density lipoproteins (IDL, LDL). LDL, as a major cholesterol carrier, serves to transport cholesterol to peripheral tissues to use through LDL receptor (LDLR). To remove the excess accumulated cholesterol from peripheral tissues, cholesterol is transported through lymphatics, veins, and back to the liver for excretion, a process called reverse cholesterol transport (RCT). The high-density lipoprotein (HDL) plays an important role in removing cholesterol through RCT. Lipid free ApoA1 picks up free cholesterol from peripheral cells through ATP binding cassette transporter A1 (ABCA1) and forms preβ-HDL. Preβ-HDL travels through lymphatics to the vein, where preβ-HDL can be further modified to become α-HDL and removed through direct uptake by HDL receptor, scavenger receptor B1 (SR-B1).

FIGURE 2

Lymphatic dependent reverse cholesterol transport within the peripheral tissues. HDL particles cross the vascular endothelium from plasma into interstitial fluid. Lipid-poor ApoA1 facilitates cellular cholesterol efflux through ABCA1-mediated pathway to form preβ-HDL. Lymphatic capillaries have discontinuous “button-like” junctions, which are permeable for optimal fluid uptake. Lymphatic flow is driven by the pumping action of downstream collecting lymphatic vessels (not depicted). Ultimately, lymph ends up in the thoracic duct that crosses the lymphovenous valve and drains into the subclavian vein.

FIGURE 3

Lymphatic dependent reverse cholesterol transport within the atherosclerotic plaque. In the context of the atherosclerotic plaque environment, removal of plaque cholesterol may be impaired by oxidation and modification of ApoA1 that prevents its ability to accept cholesterol from foam cells to form HDL. Movement of the HDL-cholesterol out of plaques occurs in the direction of interstitial fluid flow with removal likely occurring in adventitial lymphatic vessels.