Cyclodextrins as catalysts for the removal of cholesterol from macrophage foam cells.
Low concentrations of cyclodextrins (< 1.0 mM) added to serum act catalytically, accelerating the exchange of cholesterol between cells and lipoproteins. J774 macrophages incubated with serum and 2-hydroxypropyl-beta-cyclodextrin (< or = 1 mM) released fivefold more labeled cholesterol than with serum alone. Increased efflux was not accompanied by a change in cell cholesterol mass; thus, cyclodextrin functioned as a cholesterol shuttle, enhancing cholesterol bidirectional flux without changing the equilibrium cholesterol distribution between cells and medium. The addition of phospholipid vesicles to serum and cyclodextrin shifted the equilibrium distribution to favor the medium, producing rapid and extensive depletion of cell cholesterol mass. The combination of serum, phospholipid vesicles, and cyclodextrin also stimulated the rapid clearance of both free and esterified cholesterol from mouse peritoneal macrophages loaded with free and esterified cholesterol. This study: (a) demonstrates that a compound can function as a catalyst to enhance the movement of cholesterol between cells and serum, (b) illustrates the difference between cholesterol exchange and net transport in a cell/serum system, (c) demonstrates how net movement of cholesterol is linked to concentration gradients established by phospholipids, (d) provides a basis for the development of the shuttle/sink model for the first steps in reverse cholesterol transport, (e) validates the model using artificial shuttles (cyclodextrins) and sinks (large unilamellar vesicles), and (f) suggests that cyclodextrin-like cholesterol shuttles might be of pharmacological significance in treating unstable atherosclerotic plaques.
Atger
V M
VM
Hôpital Broussais, Paris, France.
de la Llera Moya
M
M
Stoudt
G W
GW
Rodrigueza
W V
WV
Phillips
M C
MC
Rothblat
G H
GH
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002384:Catalysis; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D003505:Cyclodextrins / Q000097:blood / Q000494:pharmacology*; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008081:Liposomes / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D008081:Liposomes; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002784:Cholesterol