Lipoprotein modification and macrophage uptake: role of pathologic cholesterol transport in atherogenesis.
Low-density lipoprotein (LDL) is a major extracellular carrier of cholesterol and, as such, plays important physiologic roles in cellular function and regulation of metabolic pathways. However, under pathologic conditions of hyperlipidemia, oxidative stress and/or genetic disorders, specific components of LDL become oxidized or otherwise modified, and the transport of cholesterol by modified LDL is diverted from its physiologic targets toward excessive cholesterol accumulation in macrophages and the formation of macrophage "foam" cells in the vascular wall. This pathologic deposition of modified lipoproteins and the attendant pro-inflammatory reactions in the artery wall lead to the development of atherosclerotic lesions. Continued accumulation of immunogenic modified lipoproteins and a pro-inflammatory milieu result in the progression of atherosclerotic lesions, which may obstruct the arterial lumen and/or eventually rupture and thrombose, causing myocardial infarction or stroke. In this review, we survey mechanisms of LDL modification and macrophage lipoprotein uptake, including results of recent in vivo experiments, and discuss unresolved problems and controversial issues in this growing field. Future directions in studying foam cell formation may include introducing novel animal models, such as hypercholesterolemic zebrafish, enabling dynamic in vivo observation of macrophage lipid uptake.
Miller
Yury I
YI
Department of Medicine, University of California, San Diego, La Jolla, CA 92037-0682, USA. yumiller@ucsd.edu
Choi
Soo-Ho
SH
Fang
Longhou
L
Tsimikas
Sotirios
S
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000503:physiopathology*; D018955:CD36 Antigens / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism*; D005487:Foam Cells / Q000502:physiology; D006418:Heme / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D023421:Models, Animal; D019255:NADPH Oxidases / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism; D010587:Phagocytosis; D010873:Pinocytosis; D011973:Receptors, LDL / Q000502:physiology; D051117:Scavenger Receptors, Class A / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D015027:Zebrafish
D018955:CD36 Antigens; D008078:Cholesterol, LDL; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D051117:Scavenger Receptors, Class A; D051197:Toll-Like Receptor 4; C099252:oxidized low density lipoprotein; D006418:Heme; D002784:Cholesterol; D009195:Peroxidase; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases