title: High-capacity selective uptake of cholesteryl ester from native LDL during macrophage foam cell formation.
abstract: Macrophage foam cells are a defining pathologic feature of atherosclerotic lesions. Recent studies have demonstrated that at high concentrations associated with hypercholesterolemia, native LDL induces macrophage lipid accumulation. LDL particles are taken up by macrophages as part of bulk fluid pinocytosis. However, the uptake and metabolism of cholesterol from native LDL during foam cell formation has not been clearly defined. Previous reports have suggested that selective cholesteryl ester (CE) uptake might contribute to cholesterol uptake from LDL independently of particle endocytosis. In this study we demonstrate that the majority of macrophage LDL-derived cholesterol is acquired by selective CE uptake in excess of LDL pinocytosis and degradation. Macrophage selective CE uptake does not saturate at high LDL concentrations and is not down-regulated during cholesterol accumulation. In contrast to CE uptake, macrophages exhibit little selective uptake of free cholesterol (FC) from LDL. Following selective uptake from LDL, CE is rapidly hydrolyzed by a novel chloroquine-sensitive pathway. FC released from LDL-derived CE hydrolysis is largely effluxed from cells but also is subject to ACAT-mediated reesterification. These results indicate that selective CE uptake plays a major role in macrophage metabolism of LDL.
authors: Departments of Internal Medicine and Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536.
authors: Jason M
authors: JM
authors: Meyer
authors: Department of Veterans Affairs Medical Center, Lexington, KY 40502; Departments of Internal Medicine and Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536; Barnstable Brown Kentucky Diabetes and Obesity Center, University of Kentucky, Lexington, KY 40536.
authors: Ailing
authors: A
authors: Ji
authors: Department of Veterans Affairs Medical Center, Lexington, KY 40502; Departments of Internal Medicine and Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536; Barnstable Brown Kentucky Diabetes and Obesity Center, University of Kentucky, Lexington, KY 40536.
authors: Lei
authors: L
authors: Cai
authors: Department of Veterans Affairs Medical Center, Lexington, KY 40502; Departments of Internal Medicine and Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536; Barnstable Brown Kentucky Diabetes and Obesity Center, University of Kentucky, Lexington, KY 40536. Electronic address: dvwest1@uky.edu.
authors: Deneys R
authors: DR
authors: van der Westhuyzen
mesh_terms: D000818:Animals; D002788:Cholesterol Esters / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D010873:Pinocytosis
chemical_list: D002788:Cholesterol Esters; D008078:Cholesterol, LDL