title: Cyclodextrins differentially mobilize free and esterified cholesterol from primary human foam cell macrophages.
abstract: Human monocyte-derived foam cell macrophages (HMFCs) are resistant to cholesterol efflux mediated by physiological acceptors. The role of the plasma membrane in regulating depletion of free cholesterol (FC) and of cholesteryl ester (CE) was investigated using cyclodextrins (CDs). HMFCs were incubated in media containing CDs (1.0 mg/ml, approximately 0.7 mM) with low [hydroxypropyl-beta-CD (HP-CD)] or high [trimethyl-beta-CD (TM-CD)] affinity for cholesterol in the presence or absence of phospholipid vesicles (PLVs). Low-affinity HP-CD caused minimal cholesterol efflux on its own, but HP-CD+ PLV depleted cell FC and CE to 54.5 +/- 6.7% of control by 24 h. TM-CD depleted FC at least as well as HP-CD+PLV but without depleting CE, even when combined with PLV. This was not explained by acceptor saturation, instability of PLV vesicles, de novo cholesterol synthesis, kinetically distinct cholesterol pools, or inhibition of CE hydrolysis. TM-CD did, however, deplete CE when lower concentrations of TM-CD were combined with PLV and when acetyl-CoA cholesteryl acyltransferase was inhibited. TM-CD caused much greater depletion of plasma membrane cholesterol than HP-CD without depleting plasma membrane sphingomyelin. It is concluded that differential depletion of plasma membrane cholesterol pools regulates cholesterol efflux and CE clearance in human macrophages.
authors.affiliation: Heart Research Institute, Camperdown, Sydney New South Wales, Australia.
authors.forename: Sue M
authors.initials: SM
authors.lastname: Liu
authors.forename: Anne
authors.initials: A
authors.lastname: Cogny
authors.forename: Maaike
authors.initials: M
authors.lastname: Kockx
authors.forename: Roger T
authors.initials: RT
authors.lastname: Dean
authors.forename: Katharina
authors.initials: K
authors.lastname: Gaus
authors.forename: Wendy
authors.initials: W
authors.lastname: Jessup
authors.forename: Leonard
authors.initials: L
authors.lastname: Kritharides
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism*; D003505:Cyclodextrins / Q000494:pharmacology*; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D050356:Lipid Metabolism; D008081:Liposomes / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014316:Tritium
chemical_list: D000924:Anticholesteremic Agents; D002788:Cholesterol Esters; D003505:Cyclodextrins; D008081:Liposomes; D014316:Tritium; D002784:Cholesterol; D002785:Sterol O-Acyltransferase