CYCLODEXTRINS AS CATALYSTS FOR THE REMOVAL OF CHOLESTEROL FROM MACROPHAGE FOAM CELLS

Low concentrations of cyclodextrins (< 1.0 mM) added to serum act cata lytically, accelerating the exchange of cholesterol between cells and lipoproteins. J774 macrophages incubated with serum and 2-hydroxypropy l-beta-cyclodextrin (less than or equal to 1 mM) released fivefold mor e labeled cholesterol than with serum alone. Increased efflux was not accompanied by a change in cell cholesterol mass; thus, cyclodextrin f unctioned as a cholesterol shuttle, enhancing cholesterol bidirectiona l flux without changing the equilibrium cholesterol distribution betwe en cells and medium. The addition of phospholipid vesicles to serum an d cyclodextrin shifted the equilibrium distribution to favor the mediu m, producing rapid and extensive depletion of cell cholesterol mass. T he 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 cho lesterol. This study: (a) demonstrates that a compound can function as a catalyst to enhance the movement of cholesterol between cells and s erum, (b) illustrates the difference between cholesterol exchange and net transport in a cell/serum system, (c) demonstrates how net movemen t of cholesterol is linked to concentration gradients established by p hospholipids, (d) provides a basis for the development of the shuttle/ sink model for the first steps in reverse cholesterol transport, (e) v alidates 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 trea ting unstable atherosclerotic plaques.