title: Sterol efflux is impaired from macrophage foam cells selectively enriched with 7-ketocholesterol.
abstract: The aim of the present study was to investigate whether impairment of cholesterol efflux previously found from mouse peritoneal macrophages loaded with oxidized low density lipoprotein (OxLDL) could be ascribed to the presence of oxysterols in these cells. 7-Ketocholesterol (7KC), the major oxysterol present in OxLDL-loaded cells, was selectively incorporated into unoxidized LDL, which was subsequently acetylated to produce a high uptake form. Mouse macrophages incubated with 7KC-enriched acetylated LDL (7kAcLDL) did not reveal cytotoxicity judged by cell protein and trypan blue exclusion. A large proportion of cellular 7KC was esterified, indicating that it is a substrate for acyl CoA:cholesterol acyltransferase. Cholesterol efflux from mouse macrophages loaded with 7kAcLDL, using apoA-I as a sterol acceptor, was impaired in cells containing >50 nmol of 7KC/mg of cell protein compared with cells loaded with oxysterol-free acetylated LDL. Thus impairment of cholesterol efflux could be reproduced in cells loaded with 7kAcLDL containing similar proportions of 7KC as OxLDL. 7KC itself was exported very poorly, even when the levels of 7KC in the cells were low. These results suggest that oxysterols present in foam cells in vitro can affect reverse sterol transport and may be potentially important in foam cell formation in vivo.
authors.affiliation: Cell Biology Unit, Heart Research Institute, 145 Missenden Road, Camperdown New South Wales 2050, Australia.
authors.forename: I C
authors.initials: IC
authors.lastname: Gelissen
authors.forename: A J
authors.initials: AJ
authors.lastname: Brown
authors.forename: E L
authors.initials: EL
authors.lastname: Mander
authors.forename: L
authors.initials: L
authors.lastname: Kritharides
authors.forename: R T
authors.initials: RT
authors.lastname: Dean
authors.forename: W
authors.initials: W
authors.lastname: Jessup
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001769:Blood / Q000378:metabolism; D002451:Cell Compartmentation; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004951:Esterification; D005487:Foam Cells / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D007653:Ketocholesterols / Q000494:pharmacology*; D008074:Lipoproteins / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D051379:Mice
chemical_list: D016632:Apolipoprotein A-I; D002788:Cholesterol Esters; D007653:Ketocholesterols; D008074:Lipoproteins; D008077:Lipoproteins, LDL; C032629:acetyl-LDL; C099252:oxidized low density lipoprotein; D002784:Cholesterol; C003001:7-ketocholesterol