Abstract 283: Novel Mechanism of Low-Density Lipoprotein--Derived Cholesteryl Ester Uptake and Hydrolysis During Macrophage Foam Cell Formation

Abstract

Macrophage foam cells are a defining pathologic feature of atherosclerotic lesions. Classically, scavenger receptor-mediated uptake of oxidized or enzyme-modified LDL is cited as a mechanism for foam cell formation. Recent studies have demonstrated that at high concentrations, native LDL can also induce macrophage lipid accumulation. LDL particles are taken up by macrophages as part of bulk fluid pinocytosis. However, the uptake and metabolism of cholesterol derived from native LDL during macrophage foam cell formation has not been clearly defined. Previous studies suggested that selective CE uptake might contribute to cholesterol uptake independently of LDL endocytosis. In this study we demonstrate that the majority of cholesterol taken up from LDL is acquired by selective CE uptake and not by pinocytosis and LDL degradation. CE uptake does not saturate at high LDL concentrations and is not down-regulated during cholesterol accumulation. LDL modification and scavenger receptors do not appear to play a major role in macrophage selective CE uptake. Following uptake from LDL, CE is rapidly hydrolyzed in macrophages by a novel chloroquine- and temperature-sensitive pathway. Our findings suggest that selective CE uptake plays a major role in macrophage cholesterol homeostasis during foam cell formation.