The origin and properties of free cholesterol potential gradients in plasma, and their relation to atherogenesis.

The aqueous solubilities of most lipids in lipoproteins are so low that their transfer between lipoproteins and cell membranes depends on random (collision) or specific (receptor-mediated) physical interaction between donor and acceptor interfaces, or the activity of transfer proteins which serve to increase the solubility of lipids in the aqueous phase (1). However, the solubility of cholesterol, although small (critical micelle concentration (CMC) -3 X IO-' M) (2), is sufficient for simple Fick diffusion to account for a major part of the observed flux of cholesterol between different lipoprotein particles, or between lipoproteins and cell membranes (Table 1). A similar identity has been found for the activation energies of cholesterol transfer between cell membranes and lipoproteins, and between synthetic lipid vesicles. When bidirectional flux rates are equal (for example, between cell membranes and unfractionated native normal plasma, when plasma cholesterol content is not perturbed by esterification), there is no spontaneous net transport of cholesterol into or out of the cell (6). When 1ecithin:cholesterol acyltransferase (LCAT) in plasma is active, and by esterification reduces the effective concentration (i.e., chemical potential) of cholesterol in the plasma in the face of an unchanged efflux of cholesterol from the adjacent cell membranes (3,6), its effect overall is to catalyze a compensatory net transport of free cholesterol from the cell to the plasma medium. This is compensated in vivo by cholesterogenesis within the affected cell, and by the entry of new lipoprotein cholesterol from those cells that secrete lipoproteins into plasma, which reduces or nullifies the induced cell-toplasma chemical potential gradient of cholesterol. From the same principles, it follows that if the chemical potential of cholesterol in a plasma lipoprotein species is higher than that in the other lipoproteins or in the cell membranes, cholesterol will flow down its gradient to such cells or lipoproteins until their free cholesterol content reaches its new steady state. If the acceptor lipoproteins in plasma (by the activity of LCAT) or cells (by the action of acyl CoA:cholesterol acyltransferase, ACAT) remove the cholesterol transferred from the equilibrium by the synthesis of esterified cholesterol, the flow of cholesterol will continue indefinitely, as long as the supply of cholesterol-rich donor lipoproteins continues. This process will also be governed by the thermodynamic parameters shown in Table 1. Two arguments in particular can be advanced against a significant role for thermodynamic (i.e., non-receptor) processes in cholesterol transport between plasma lipoproteins and cells, and the regulation of cellular cholesterol metabolism, particularly in relation to the cholesterol accumulation that occurs in atherosclerosis. i) In the plasma of many of those at risk for atherosclerosis, e.g., hyperbetalipoproteinemics (7), the composition, and, in particular, the cholesterol content, of the lipoproteins is normal. ii) Only that lipoprotein cholesterol interiorized by receptor mechanisms is effective in mediating changes in cellular cholesterol metabolism (8). Neither argument, however, is likely to be valid.