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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1910.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Inhibition of Cholesteryl Ester Transfer Protein Activity by JTT-705 Increases Apolipoprotein E–Containing High-Density Lipoprotein and Favorably Affects the Function and Enzyme Composition of High-Density Lipoprotein in Rabbits

Bo Zhang; Ping Fan; Eiso Shimoji; Huali Xu; Kazuma Takeuchi; Cheng Bian; Keijiro Saku

From the Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.

Correspondence to Dr Bo Zhang, Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma Jonan-ku, Fukuoka 814-0180, Japan. E-mail bozhang{at}fukuoka-u.ac.jp

Background— Inhibition of cholesteryl ester transfer protein (CETP) is an efficient way to increase high-density lipoprotein (HDL) levels in humans. We investigated the effects of the inhibition of CETP activity by a CETP inhibitor, JTT-705, on the function and composition of HDL particles.

Methods and Results— Japanese white rabbits were fed either normal rabbit chow LRC-4 (n=10) or a food admixture of LRC-4 and 0.75% JTT-705 (n=10) for 7 months. JTT-705 significantly inhibited CETP activities, increased HDL cholesterol (HDL-C) levels and the ratio of HDL₂-C/HDL₃-C, and decreased the fractional esterification rate of cholesterol in HDL, indicating preferentially increased large HDL particles. Treatment with JTT-705 increased all of the 3 charge-based HDL subfractions as determined by capillary isotachophoresis: fast-migrating, intermediate-migrating, and slow-migrating HDL. The percentage of slow HDL, ie, apolipoprotein E (apoE)-containing HDL and levels of apoE in HDL fraction, was also increased. JTT-705 treatment increased serum paraoxonase activity and HDL-associated platelet-activating factor acetylhydrolase activity, but decreased the plasma lysophosphatidylcholine concentration.

Conclusion— Inhibition of CETP activity by JTT-705 not only increased the quantity of HDL, including HDL-C levels and charge-based HDL subfractions, but also favorably affected the size distribution of HDL subpopulations and the apolipoprotein and enzyme composition of HDL in rabbits.

The effects of CETP inhibition on the function and composition of HDL particles were examined in rabbits. JTT-705 significantly inhibited CETP activities, decreased FERHDL values, and increased apoE-containing HDL and activities of paraoxonase and HDL-associated PAF-AH. In conclusion, inhibition of CETP activity favorably affected the size distribution of HDL subpopulations and the apolipoprotein and enzyme composition of HDL.

Key Words: cholesteryl ester transfer protein inhibition • apolipoprotein E-containing high-density lipoprotein • capillary isotachophoresis • paraoxonase (PON1) • platelet-activating factor acetylhydrolase • lysophosphatidylcholine • rabbits

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