ROLE OF HDL APOLIPOPROTEIN E IN CELLULAR CHOLESTEROL EFFLUX - STUDIES IN APO-E KNOCKOUT TRANSGENIC MICE

The role of apo E in aspects of reverse cholesterol transport was studied in apolipoprotein E-deficient mice. These animals develop rampant atherosclerosis. The efflux of cholesterol from mouse peritoneal macrophages (MPM) was 40% lower when induced by high density lipoprotein (HDL) from apo E-deficient mice, compared to the effect of HDL from normal mice. On adding apo E to apo E-deficient HDL, cholesterol efflux from the macrophages increased by 35%, approaching the degree of efflux obtained with normal HDL, This HDL (normal or apo E-deficient)-induced cholesterol efflux was similar in peritoneal macrophages derived from both normal and apo E-deficient mice, suggesting that the HDL apo E rather than the macrophage apo E is responsible for the stimulation of cellular cholesterol efflux. On determining cholesterol efflux specifically from the macrophage plasma membrane, the revel of efflux was similar for both HDL preparations, suggesting that apo E in HDL is important for cholesterol translocation to the plasma membrane, the initial step in reverse cholesterol transport. It is concluded that the enhanced atherosclerosis in apo E-deficient mice could be related, at least partly, to the impaired efflux of LDL derived cholesterol from macrophages of the arterial wall. (C) 1994 Academic Press, Inc.