HUMAN APOLIPOPROTEINS A-I AND A-II IN CELL CHOLESTEROL EFFLUX - STUDIES WITH TRANSGENIC MICE

The first step in reverse cholesterol transport is the movement of cho lesterol out of cells onto lipoprotein accepters in the interstitial f luid. The contribution of specific lipoprotein components to this proc ess remains to be established. In this study, the role of human apolip oproteins (apo) A-I and A-II in the efflux of cellular cholesterol was investigated in transgenic mouse models in which the expression of mu rine apoA-I was abolished due to gene targeting (A-IKO). Serum from A- IKO mice and from mice expressing human apoA-I and/or human apoA-II wa s incubated with [H-3]cholesterol-labeled Fu5AH rat hepatoma cells for 4 hours at 37 degrees C. The cholesterol efflux to the serum of A-IKO mice was markedly lower than that to the serum of mice transgenic for human apoA-I (5.0+/-1.5% versus 25.0+/-4.0%). Expression of human apo A-II alone did not modify the cholesterol efflux capacity of A-IKO mou se serum. Cholesterol efflux to serum of mice expressing human apoA-II together with human apoA-I was significantly lower than that to human apoA-I mouse serum (20.0+/-12.3% versus 25.0+/-4.0%). Regression anal ysis of cholesterol efflux versus the lipid/apolipoprotein concentrati ons of mouse serum suggested that 3 independent factors contribute to determine the cholesterol efflux potential of serum: the apolipoprotei n composition of HDL, the serum concentration of HDL phospholipids, an d the presence of a small fraction of particles containing apoA-I.