title: Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1.
abstract: Macrophages clear millions of apoptotic cells daily and, during this process, take up large quantities of cholesterol. The membrane transporter ABCA1 is a key player in cholesterol efflux from macrophages and has been shown via human genetic studies to provide protection against cardiovascular disease. How the apoptotic cell clearance process is linked to macrophage ABCA1 expression is not known. Here, we identified a plasma membrane-initiated signaling pathway that drives a rapid upregulation of ABCA1 mRNA and protein. This pathway involves the phagocytic receptor brain-specific angiogenesis inhibitor 1 (BAI1), which recognizes phosphatidylserine on apoptotic cells, and the intracellular signaling intermediates engulfment cell motility 1 (ELMO1) and Rac1, as ABCA1 induction was attenuated in primary macrophages from mice lacking these molecules. Moreover, this apoptotic cell-initiated pathway functioned independently of the liver X receptor (LXR) sterol-sensing machinery that is known to regulate ABCA1 expression and cholesterol efflux. When placed on a high-fat diet, mice lacking BAI1 had increased numbers of apoptotic cells in their aortic roots, which correlated with altered lipid profiles. In contrast, macrophages from engineered mice with transgenic BAI1 overexpression showed greater ABCA1 induction in response to apoptotic cells compared with those from control animals. Collectively, these data identify a membrane-initiated pathway that is triggered by apoptotic cells to enhance ABCA1 within engulfing phagocytes and with functional consequences in vivo.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Fond
authors.forename: Chang Sup
authors.initials: CS
authors.lastname: Lee
authors.forename: Ira G
authors.initials: IG
authors.lastname: Schulman
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kiss
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D050356:Lipid Metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D048868:Adaptor Proteins, Signal Transducing; D042501:Angiogenic Proteins; D002784:Cholesterol; D000071518:Liver X Receptors; D009479:Neuropeptides; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D020830:rac1 GTP-Binding Protein; C577833:Abca1 protein, mouse; C524949:Adgrb1 protein, mouse; C510359:ELMO1 protein, mouse; C484602:Rac1 protein, mouse