Macrophage-mediated cholesterol handling in atherosclerosis.
Formation of foam cells is a hallmark at the initial stages of atherosclerosis. Monocytes attracted by pro-inflammatory stimuli attach to the inflamed vascular endothelium and penetrate to the arterial intima where they differentiate to macrophages. Intimal macrophages phagocytize oxidized low-density lipoproteins (oxLDL). Several scavenger receptors (SR), including CD36, SR-A1 and lectin-like oxLDL receptor-1 (LOX-1), mediate oxLDL uptake. In late endosomes/lysosomes of macrophages, oxLDL are catabolysed. Lysosomal acid lipase (LAL) hydrolyses cholesterol esters that are enriched in LDL to free cholesterol and free fatty acids. In the endoplasmic reticulum (ER), acyl coenzyme A: cholesterol acyltransferase-1 (ACAT1) in turn catalyses esterification of cholesterol to store cholesterol esters as lipid droplets in the ER of macrophages. Neutral cholesteryl ester hydrolases nCEH and NCEH1 are involved in a secondary hydrolysis of cholesterol esters to liberate free cholesterol that could be then out-flowed from macrophages by cholesterol ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 and SR-BI. In atherosclerosis, disruption of lipid homoeostasis in macrophages leads to cholesterol accumulation and formation of foam cells.
Division of Laboratory Medicine, Department of Molecular Genetic Diagnostics and Cell Biology, Institute of Pediatrics, Research Center for Children's Health, Moscow, Russia.
Dimitry A
DA
Chistiakov
Faculty of Medicine and St Vincent's Centre for Applied Medical Research, University of New South Wales, Sydney, NSW, Australia.|School of Medicine, University of Western Sydney, Campbelltown, NSW, Australia.|Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow, Russia.
Yuri V
YV
Bobryshev
Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow, Russia.|Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Sciences, Moscow, Russia.|Department of Biophysics, Biological Faculty, Moscow State University, Moscow, Russia.
Alexander N
AN
Orekhov
D000818:Animals; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism*; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism
D002784:Cholesterol
atherogenesis; atherosclerosis; cholesterol; foam cells; lipoproteins; macrophages