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

DOI Web Site 8 Citations
  • Bo Zhang
    From the Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
  • Ping Fan
    From the Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
  • Eiso Shimoji
    From the Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
  • Huali Xu
    From the Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
  • Kazuma Takeuchi
    From the Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
  • Cheng Bian
    From the Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
  • Keijiro Saku
    From the Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.

Abstract

<jats:p> <jats:bold> <jats:italic>Background—</jats:italic> </jats:bold> 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. </jats:p> <jats:p> <jats:bold> <jats:italic>Methods and Results—</jats:italic> </jats:bold> 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 HDL <jats:sub>2</jats:sub> -C/HDL <jats:sub>3</jats:sub> -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. </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusion—</jats:italic> </jats:bold> 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. </jats:p>

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