Abstract 679: Variations in the Expression of Cholesterol Ester Hydrolase in Macrophages from Human Subjects and its Relationship to Coronary Artery Disease (CAD): A Pilot Study
Cholesterol ester hydrolase (CEH) catalyses the rate limiting step in free cholesterol efflux from macrophage foam cells and intracellular CEH levels negatively correlate with lipid accumulation in foam cells and susceptibility to atherosclerosis. We have demonstrated that macrophage-specific transgenic expression of CEH enhances cholesterol efflux from foam cells and reduces lesions in athero-susceptible LDLR−/− mice. In the present study we tested the hypothesis that expression of CEH in blood-derived macrophages and the cholesterol efflux potential of serum from human subjects correlates with the disease status. Human subjects with (n=5, age 47–72 y) or without (n=7, age 50 –71 y) established CAD were enrolled. All subjects with established disease were on Statins and the serum lipid profiles (Total cholesterol, 198±16 vs 216±17; LDL-C, 109±13 vs 105±18; and HDL-C, 52±8 vs 63±10) were not significantly different between the two groups. Blood monocytes were isolated and cultured in autologous serum. Total RNA was prepared after 7-days and macrophage CEH mRNA levels determined by Real Time PCR and expressed as copy number/ng total RNA. Serum from the same subjects was used to determine the cholesterol efflux potential (% efflux observed with 4% serum at 6h) using a human monocyte/macrophage cell line THP1-derived cell system (THP1-CEH cells) where efflux is directly related to the efflux potential of exogenous acceptor such as serum. CEH mRNA levels in macrophages were positively correlated with HDL-C levels (r2=0.69) in subjects with no established disease and who were not on statins. The cholesterol efflux potential of serum from subjects without any disease was significantly higher than those with established disease (32.41±0.69 vs 26.72±0.81, p<0.001).
Conclusions: The observed correlation between HDL-C and CEH mRNA levels suggests that lower CEH levels, that would limit free cholesterol efflux from foam cells, may represent another risk factor for CAD. Although the HDL-C levels were not significantly different between the two groups, the significantly lower efflux observed with serum from subjects with established disease suggests that functionality of HDL (efflux potential) would be a better risk predictor than HDL-C levels alone.