Mc. Phillips et al., MECHANISMS OF HIGH-DENSITY LIPOPROTEIN-MEDIATED EFFLUX OF CHOLESTEROLFROM CELL PLASMA-MEMBRANES, Atherosclerosis (Amsterdam), 137, 1998, pp. 13-17
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
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