Abstract

High-density lipoproteins are the putative vehicles for cholesterol removal from monocyte-derived macrophages, which are an important cell type in all stages of atherosclerosis. The role of HDL 2, an HDL subclass that accounts for most variation in plasma HDL-cholesterol concentration, in cholesterol metabolism in monocyte-derived macrophages is not known. In this study, the dose-dependent effects of HDL 2 on cellular cholesterol mass, efflux, and esterification, and on cellular cholesteryl ester (CE) hydrolysis using the mouse macrophage P388D1 cell line was investigated. HDL 2 at low concentrations (40 μg protein/ml) decreased CE content without affecting cellular free cholesterol content (FC), CE hydrolysis, or cholesterol biosynthesis. In addition, HDL 2 at low concentrations reduced cellular acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity and increased FC efflux from macrophages. Thus, HDL 2 has two potential roles in reverse cholesterol transport. In one, HDL 2 is an acceptor of macrophage FC. In the other, more novel role, HDL 2 increases the availability of macrophage FC through the inhibition of ACAT. Elucidation of the mechanism by which HDL 2 inhibits ACAT could identify new therapeutic targets that enhance the transfer of cholesterol from macrophages to the liver.

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