Evaluation of Pathways for the Cellular Uptake of High Density Lipoprotein Cholesterol Esters in Rabbits

Cholesterol esters (CE) formed in HDL by lecithin:cholesterol acyltransferase are thought to mediate the return of cholesterol from extrahepatic tissues to the liver for excretion or reutilization. Several pathways may be involved in that process. Tracer kinetics were used to estimate the contributions of the various pathways to cellular uptake of HDL CE in rabbits. Tracers of HDL CE, HDL apo A-I, LDL apo B, and VLDL CE were simultaneously injected intravenously. Plasma decays were followed for 24 h in 4 lipoprotein pools: HDL without apo E, HDL with apo E, LDL, and VLDL. Kinetic analysis of the resulting plasma decay curves revealed that the preponderance of plasma CE (greater than 90%) originated in the HDL fraction. About 70% of HDL CE were cleared from plasma after transfer to LDL and VLDL, 20% were cleared directly from the HDL pool without HDL particle uptake ("selective" uptake), and 10% were cleared in HDL particles (including particles containing apo E). Since rabbits have about four times the plasma cholesterol ester transfer activity of man, and since the transfer pathway must compete with the selective uptake pathway, these results make it likely that selective uptake plays a substantial role in humans in the clearance of HDL CE.