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A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits

Nature volume 406, pages 203–207 (2000)Cite this article

Abstract

Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates the exchange of cholesteryl ester in high-density lipoprotein (HDL) for triglyceride in very low density lipoprotein (VLDL)1,2. This process decreases the level of anti-atherogenic HDL cholesterol and increases pro-atherogenic VLDL and low density lipoprotein (LDL) cholesterol, so CETP is potentially atherogenic3,4,5,6,7,8,9. On the other hand, CETP could also be anti-atherogenic10,11,12,13,14, because it participates in reverse cholesterol transport (transfer of cholesterol from peripheral cells through the plasma to the liver)15. Because the role of CETP in atherosclerosis remains unclear, we have attempted to develop a potent and specific CETP inhibitor. Here we describe CETP inhibitors that form a disulphide bond with CETP, and present one such inhibitor (JTT-705) that increases HDL cholesterol, decreases non-HDL cholesterol and inhibits the progression of atherosclerosis in rabbits. Our findings indicate that CETP may be atherogenic in vivo and that JTT-705 may be a potential anti-atherogenic drug.

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Figure 1: Effect of JTT-705 on the activity of wild-type and mutant CETP proteins.
Figure 2: Effect of JTT-705 on plasma CETP activity and HDL-C level in rabbits fed regular chow.
Figure 3: Cholesterol distribution in plasma lipoproteins from control, JTT-705-treated and simvastatin-treated rabbits at three months.
Figure 4: Typical photographs of aortas from control, JTT-705-treated and simvastatin-treated rabbits.

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Acknowledgements

We thank Y. Iwamoto, M. Maki and T. Sotani for their assistance with the experiments, and A. Mizushima and M. Kamada for advice. We also thank H. Koizumi and the staff of the Toxicology Research Laboratories at the Central Pharmaceutical Research Institute of JT Inc.

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Authors and Affiliations

  1. Biological/Pharmacological Research Laboratories,

    Hiroshi Okamoto, Fumihiko Yonemori & Korekiyo Wakitani

  2. Chemical Research Laboratories, Central Pharmaceutical Research Institute, JT Inc., 1-1 Murasaki-cho, Takatsuki, 569-1125, Osaka, Japan

    Kimiya Maeda & Hisashi Shinkai

  3. Pharmaceutical Frontier Research Laboratories, Central Pharmaceutical Research Institute, JT Inc., 13-2 Fukuura 1-chome, Kanazawa-ku, Yokohama, 236-0004, Kanagawa, Japan

    Takashi Minowa

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  1. Hiroshi Okamoto
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Correspondence to Hiroshi Okamoto.

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Okamoto, H., Yonemori, F., Wakitani, K. et al. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature 406, 203–207 (2000). https://doi.org/10.1038/35018119

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