Abstract 1025: Importance of Macrophage Cholesteryl Ester Transfer Protein (CETP) for Determining Serum Cholesteryl Ester Transfer Activity and Atherosclerosis
CETP inhibition is a promising new therapeutic strategy to increase HDL levels and reduce atherosclerosis. Abundant amounts of CETP are found in macrophage foam cells in the arterial wall, where it has been implicated in the efflux of cholesterol. Recently, we showed that CETP derived from macrophages induces redistribution of cholesterol from HDL to VLDL and promotes the development of atherosclerotic lesions in LDL receptor knockout mice that endogenously lack CETP. To confirm the quantitative importance of macrophage-derived CETP for determining plasma CETP activity in the presence of endogenous CETP production, in the current study the effect of specific disruption of macrophage CETP in human CETP transgenic (Tg) mice was determined by transplantation of wildtype (WT) bone marrow into CETP Tg mice. At 8 weeks after transplantation, CETP activity was only 23±3 nmol/ml/h in WT → CETP Tg mice as compared to 50±3 nmol/ml/h in control CETP Tg → CETP Tg animals (p<0.0001). The observed reduction in plasma CETP activity levels coincided with 2-fold lower (p=0.029) CETP mRNA expression levels in the liver (0.18±0.03 for control CETP Tg → CETP Tg animals and 0.09±0.02 for WT → CETP Tg mice). In contrast to the findings in the LDL receptor knockout mice, in which the removal of VLDL from the circulation is severely impaired, in CETP Tg mice no effect of disruption of macrophage CETP production was observed on serum cholesterol levels. In addition, no differences were observed in atherosclerotic lesion size (74±10*103 μm2 for CETP Tg → CETP Tg animals (n=9) and 75±10*103 μm2 for WT → CETP Tg mice (n=8)) after 8 weeks on a high-cholesterol diet, suggesting that macrophage CETP production does not influence lesion development locally in the arterial wall. In agreement, in vitro studies confirmed that CETP expression has no effect on macrophage cholesterol efflux (apoAI efflux: 12±2% for WT and 9±1% for CETP Tg macrophages and HDL efflux: 27±1% and 28±2%, respectively). In conclusion, macrophage CETP is an important contributor to the plasma cholesterol ester transfer activity. Furthermore, its effects on atherosclerotic lesion development are solely the result of systemic effects on cholesterol redistribution and not of local effects on cholesterol efflux in the arterial wall.