on August 26, 2004
Published online before print August 26, 2004, doi: 10.1161/01.ATV.0000143389.00252.bc
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Submitted on July 8, 2004
Accepted on August 13, 2004
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 *;
From the Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
* To whom correspondence should be addressed. 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.
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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