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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 (nϭ10) or a food admixture of LRC-4 and 0.75% JTT-705 (nϭ10) for 7 months. JTT-705 significantly inhibited CETP activities, increased HDL cholesterol (HDL-C) levels and the ratio of HDL 2 -C/HDL 3 -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. Key Words: cholesteryl ester transfer protein inhibition Ⅲ apolipoprotein E-containing high-density lipoprotein Ⅲ capillary isotachophoresis Ⅲ paraoxonase (PON1) Ⅲ platelet-activating factor acetylhydrolase Ⅲ lysophosphatidylcholine Ⅲ rabbits I ncreased levels of low-density lipoprotein cholesterol (LDL-C) and reduced levels of high-density lipoprotein cholesterol (HDL-C) are known risk factors for coronary heart disease (CHD). The balance between HDL-C and LDL-C is known to be important in predicting the risk of CHD. 1 Although statin drugs potently lower LDL-C levels, their ability to raise HDL levels is limited. HDL helps to protect against atherosclerosis mainly because of its role in the reverse cholesterol transport process and its anti-oxidative and anti-inflammatory properties. Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl ester (CE) from HDL to apolipoprotein B (apoB)-containing lipoproteins and of triglyceride from triglyceride-rich remnants to HDL and LDL. 2 The HDL level has been shown to be influenced by CETP based on the fact that patients with genetic CETP deficiency have extremely high levels of HDL. 3 Although whether CETP is anti-atherogenic or proatherogenic depends on the metabolic background, and the exact role that CETP plays in atherosclerosis is still controversial, inhibition of CETP activity by small molecular CETP inhibitors, including JTT-705 and torcetrapib, has been shown to be an efficient way to raise HDL levels in subjects with normal 4,5 and low HDL-C levels. 6 HDL consists of heterogeneous particles that differ in density and size. Inhibition of CETP activity by torcetrapib in subjects with low HDL-C levels caused a much greater percentage increase in HDL 2 -C levels than in HDL 3 -C levels, and increased large HDL particles as determined by nuclear magnetic ...

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