title: Microdomains, Inflammation, and Atherosclerosis.
abstract: Elevated levels of cholesteryl ester (CE)-enriched apoB containing plasma lipoproteins lead to increased foam cell formation, the first step in the development of atherosclerosis. Unregulated uptake of low-density lipoprotein cholesterol by circulating monocytes and other peripheral blood cells takes place through scavenger receptors and over time causes disruption in cellular cholesterol homeostasis. As lipoproteins are taken up, their CE core is hydrolyzed by liposomal lipases to generate free cholesterol (FC). FC can be either re-esterified and stored as CE droplets or shuttled to the plasma membrane for ATP-binding cassette transporter A1-mediated efflux. Because cholesterol is an essential component of all cellular membranes, some FC may be incorporated into microdomains or lipid rafts. These platforms are essential for receptor signaling and transduction, requiring rapid assembly and disassembly. ATP-binding cassette transporter A1 plays a major role in regulating microdomain cholesterol and is most efficient when lipid-poor apolipoprotein AI (apoAI) packages raft cholesterol into soluble particles that are eventually catabolized by the liver. If FC is not effluxed from the cell, it becomes esterified, CE droplets accumulate and microdomain cholesterol content becomes poorly regulated. This dysregulation leads to prolonged activation of immune cell signaling pathways, resulting in receptor oversensitization. The availability of apoAI or other amphipathic α-helix-rich apoproteins relieves the burden of excess microdomain cholesterol in immune cells allowing a reduction in immune cell proliferation and infiltration, thereby stimulating regression of foam cells in the artery. Therefore, cellular balance between FC and CE is essential for proper immune cell function and prevents chronic immune cell overstimulation and proliferation.
authors.affiliation: From the Division of Endocrinology, Metabolism and Clinical Nutrition, Department of Medicine and Senior Investigator, Blood Research Institute, BloodCenter of Wisconsin (M.G.S.-T.) and Department of Pharmacology and Toxicology (M.J.T.), Medical College of Wisconsin, Milwaukee, WI. msthomas@mcw.edu.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sorci-Thomas
authors.affiliation: From the Division of Endocrinology, Metabolism and Clinical Nutrition, Department of Medicine and Senior Investigator, Blood Research Institute, BloodCenter of Wisconsin (M.G.S.-T.) and Department of Pharmacology and Toxicology (M.J.T.), Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thomas
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000818:Animals; D001158:Arteries / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000276:immunology / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D004951:Esterification; D005487:Foam Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006868:Hydrolysis; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation; D021962:Membrane Microdomains / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D002784:Cholesterol
keywords: apolipoprotein A-I; atherosclerosis; cholesterol; inflammation; membrane microdomains