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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, OBJECTIVE, RESULTS. Meshes: ATP Binding Cassette Transporter 1, ATP Binding Cassette Transporter, Subfamily G, Member 1, ATP-Binding Cassette Transporters, Actins, Animals, Cell Membrane, Cell Movement, Cells, Cultured, Chemotaxis, Cholesterol, Guanosine Triphosphate, Lipoproteins, Macrophages, Mice, Mice, Knockout, Models, Animal, Neuropeptides, Signal Transduction, rac GTP-Binding Proteins, rac1 GTP-Binding Protein.
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Does deletion of ABCA1 and ABCG1 impair macrophage migration because of increased Rac1 signaling? Context: Reduced plasma cholesterol and increased high-density lipoprotein (HDL) levels promote regression of atherosclerosis, in a process characterized by lipid unloading and emigration of macrophages from lesions. In contrast free cholesterol loading of macrophages leads to imbalanced Rac1/Rho activities and impaired chemotaxis. To study the role of HDL and the ATP-binding cassette transporters ABCA1 and ABCG1 in modulating the chemotaxis of macrophages. Abca1(-/-)Abcg1(-/-) mouse macrophages displayed profoundly impaired chemotaxis both in a Transwell chamber assay and in the peritoneal cavity of wild-type (WT) mice. HDL reversed impaired chemotaxis in free cholesterol-loaded WT macrophages but was without effect in Abca1(-/-)Abcg1(-/-) cells, whereas cyclodextrin was effective in both. Abca1(-/-)Abcg1(-/-) macrophages had markedly increased Rac1 activity and increased association of Rac1 with the plasma membrane (PM). Their defective chemotaxis was reversed by a Rac1 inhibitor. To gain a better understanding of the role of transporters in PM cholesterol movement, we measured transbilayer PM sterol distribution. In WT macrophages, the majority of cholesterol was located on the inner leaflet, whereas on upregulation of transporters by liver X receptor activation, PM sterol was shifted to the outer leaflet, where it could be removed by HDL. Abca1(-/-)Abcg1(-/-) macrophages showed increased PM sterol content and defective redistribution of sterol to the outer leaflet.
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Deletion of ABCA1 and ABCG1 causes an increased cholesterol content on the inner leaflet of the PM, associated with increased Rac1 PM localization, activation, and impairment of migration. ABCA1 and ABCG1 facilitate macrophage chemotaxis by promoting PM transbilayer cholesterol movement and may contribute to the ability of HDL to promote regression of atherosclerosis. Final Decision: yes