MECHANISMS OF HIGH-DENSITY LIPOPROTEIN-MEDIATED EFFLUX OF CHOLESTEROLFROM CELL PLASMA-MEMBRANES

The participation of HDL in the reverse cholesterol transport (RCT) fr om peripheral cells to the liver is critical for the antiatherogenic p roperties of this lipoprotein. Experimental results showing that efflu x of cholesterol from cells growing in culture is mediated by HDL and lipoprotein particles containing apo A-I, in particular, support this conclusion. A bidirectional flux of unesterified cholesterol molecules between the plasma membrane of cells and HDL particles in the extrace llular medium occurs. Net efflux of cholesterol mass from the cells in volves passive diffusion of cholesterol molecules through the aqueous phase and down their concentration gradient between the membrane and H DL; the concentration gradient is maintained by LCAT-mediated esterifi cation of cholesterol molecules in the HDL particles. Fully lipidated apo A-I is important in promoting this aqueous diffusion mechanism bec ause it: (1) acts as a cofactor for LCAT; and (2) solubilizes phosphol ipid into small HDL-sized particles that are efficient at absorbing ch olesterol molecules diffusing away from the cell surface. Apo A-I also exists in an incompletely lipidated state in plasma. Apo A-I molecule s in this state are able to solubilize phospholipid and cholesterol fr om the plasma membrane of cells. This membrane-microsolubilization pro cess is enhanced by enrichment of the plasma membrane with cholesterol and is the mechanism by which pre-beta-HDL particles in the extracell ular medium remove cholesterol and phospholipid from cells. The relati ve contributions in vivo of the aqueous diffusion and membrane-microso lubilization mechanisms of apo A-I-mediated cell cholesterol efflux ar e not predicted readily from cell culture experiments. Confounding iss ues are the variations with cell type and the dependence on the degree of cholesterol loading of the cell plasma membrane. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.