In human plasma, CETP facilitates the movement of neutral lipid between lipoproteins, resulting in a net exchange of triglyceride (TG) from VLDL for cholesteryl

Journal of Lipid Research Volume 54, 2013 2647 Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc. of agents that increase levels of HDL-C has been challenging, cholesteryl ester transfer protein (CETP) has emerged as a potential therapeutic target. In human plasma, CETP facilitates the movement of neutral lipid between lipoproteins, resulting in a net exchange of triglyceride (TG) from VLDL for cholesteryl ester (CE) from HDL ( 4 ). The impact of CETP on HDL metabolism was initially revealed in a series of genetic studies of Japanese families in which subjects with elevated HDL levels were found to have mutations that resulted in CETP defi ciency ( 5–7 ). However, subsequent studies examining the relationship between CETP defi ciency and CVD have been mixed. The seven-year prospective data from Honolulu Heart Study found no signifi cant relationship between heterozygous mutations of CETP and CVD ( 8 ). Furthermore, results from this study and others indicated that individuals with loss-of-function mutations in CETP who have moderate HDL-C levels could have an increased CVD risk ( 8, 9 ). However, a large-scale meta-analysis of 92 studies with 113,833 subjects found increases in HDL-C associated with reductions in CETP protein and activity were atheroprotective ( 10 ). These observations were upheld in a genome-wide association study from the Women’s Genome Health Study in which single nucleotide polymorphisms in the CETP gene were associated with an increase in HDL-C and a lower risk of developing CVD ( 11 ). In composite, these recent large-scale studies indicate CETP is proatherogenic and support the development of drugs targeting CETP. The clinical development of CETP inhibitors has also been controversial. For example, torcetrapib, a small molecule inhibitor (SMI) of CETP, demonstrated signifi cant increases in HDL-C and apoA-I as well as reductions in Abstract Due to their ability to promote positive effects across all of the lipoprotein classes, cholesteryl ester transfer protein (CETP) inhibitors are currently being developed as therapeutic agents for cardiovascular disease. In these studies, we compared an antisense oligonucleotide (ASO) inhibitor of CETP to the CETP small molecule inhibitor anacetrapib. In hyperlipidemic CETP transgenic (tg) mice, both drugs provided comparable reductions in total plasma cholesterol, decreases in CETP activity, and increases in HDL cholesterol. However, only mice treated with the antisense inhibitor showed an enhanced effect on macrophage reverse cholesterol transport, presumably due to differences in HDL apolipoprotein composition and decreases in plasma triglyceride. Additionally, the ASO-mediated reductions in CETP mRNA were associated with less accumulation of aortic cholesterol. These preliminary fi ndings suggest that CETP ASOs may represent an alternative means to inhibit that target and to support their continued development as a treatment for cardiovascular disease in man . — Bell III, T. A., M. J. Graham, R. G. Lee, A. E. Mullick, W. Fu, D. Norris, and R. M. Crooke. Antisense oligonucleotide inhibition of cholesteryl ester transfer protein enhances RCT in hyperlipidemic, CETP transgenic, LDLr / mice. J. Lipid Res. 2013. 54: 2647–2657.