BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

In Vivo Effects of CETP Inhibitory Peptides in Hypercholesterolemic Rabbit and Cholesteryl Ester Transfer Protein-Transgenic Mice

  • Cho, Kyung-Hyun (Department of Genetic Engineering, College of Natural Sciences, Kyungpook National University) ;
  • Shin, Yong-Won (Department of Genetic Engineering, College of Natural Sciences, Kyungpook National University) ;
  • Choi, Myung-Sook (Department of Food Sciences & Nutrition, College of Human Ecology, Kyungpook National University) ;
  • Bok, Song-Hae (Korea Research Institute of Bioscience and Biotechnology) ;
  • Jang, Sang-Hee (Department of Food and Nutritional Sciences, Kumi College) ;
  • Park, Yong-Bok (Department of Genetic Engineering, College of Natural Sciences, Kyungpook National University)
  • Published : 2002.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

We previously reported that cholesteryl ester transfer protein (CETP) inhibitory peptides (designated $P_{28}$ and $P_{10})$ have anti-atherogenic effects in hypercholesterolemic rabbits (Biochim. Biophys. Acta (1998) 1391, 133-144). To further investigate those effects, we studied rabbit plasma that was collected after 30 h of a $P_{28}$ or $P_{10}$ injection. We found that there is a strong correlation between the in vivo CETP inhibition effects and alterations of lipoprotein particle size distribution in rabbit plasma, as determined on an agarose gel electrophoresis and gel filtration column chromatography. In vivo effects of the peptide were observed again in C57BL/6 mice that expressed simian CETP. The $P_{28}$ or $P_{10}$ peptide ($7\;{\mu}g/g$ of body weight) that was dissolved in saline was injected subcutaneously into the mice. The $P_{28}$ injection caused the partial inhibition of plasma CETP activity up to 50%, decreasing the total plasma cholesterol concentration by 30%, and increasing the ratio of HD/total-cholesterol concentration by 150% in the CETP-transgenic (tg) mice. The CETP inhibition by the $P_{28}$ or $P_{10}$ made alterations that modulated the size re-distribution of the lipoproteins in the blood stream. Particle size of the very low (VLDL) and low density lipoproteins (LDL) from the peptide-injected group was highly decreased compared to the saline-injected group (determined on the gel filtration column chromatography). In contrast, The HDL particle size of the $P_{28}$-injected group increased compared to the control group (saline-injected). The expression level of the CETP mRNA of the $P_{28}$-injected CETP-tg mouse appeared lower than the saline-injected CETP-tg mouse. These results suggest that the injection of the CETP inhibitory peptide could affect the CETP expression level in the liver by influencing lipoprotein metabolism.

Keywords

References

  1. Abbey, M., Bastiras, S. and Calvert, G. D. (1985) Immunoprecipitation of lipid transfer protein activity by an antibody against human plasma lipid transfer protein-I. Biochim Biophys. Acta 833, 25-33. https://doi.org/10.1016/0005-2760(85)90249-8
  2. Abbey, M. and Calvert, G. D. (1989) Effects of blocking plasma lipid transfer protein activity in the rabbit. Biochim. Biophys. Acta 1003, 20-29. https://doi.org/10.1016/0005-2760(89)90093-3
  3. Agellon, L. B., Walsh, A., Hayek, T., Moulin, P., Cheng Jiang, X., Shelanski, S. A., Breslow, J. L. and Tall, A. R. (1991) Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer protein transgenic mice. J. Biol. Chem. 266, 10796-10801.
  4. Albers, J. J., Tollefson, J. H., Chen, C-H. and Steinmetz, A. (1984) Isolation and characterization of human plasma lipid transfer proteins. Arteriosclerosis 4, 49-58. https://doi.org/10.1161/01.ATV.4.1.49
  5. Allain, C. C., Poon, L. S., Chan, C. S. G., Richmond, W. and Fu, P. C. (1974) Enzymatic determination of total serum cholesterol. Clin. Chem 20, 470-475.
  6. Chen, C. H. and Albers, J. J. (1982) Characterization of proteoliposomes containing apolipoprotein A-I: a new substrate for the measurement of lecithin:cholesterol acyltransferase activity. J. Lipid Res. 23, 680-691.
  7. Cho, K. H., Lee, J. Y., Choi, M. S., Cho, J. M., Lim, J. S. and Park, Y. B. (1998) A peptide from hog plasma that inhibits human cholesteryl ester transfer protein Biochim. Biophys. Acta 1391, 133-144. https://doi.org/10.1016/S0005-2760(97)00197-5
  8. Evans, G. F., Bensch, W. R., Apelgren, L. D., Bailey, D., ,Kauffman, R. F., Bumol, T. F. and Zuckennan, S. H. (1994) Inhibition of cholesteryl ester transfer protein in nonnocholesterolemic and hypercholesterolemic hamsters: effects on HDL subspecies, quantity, and apolipoprotein distribution. J. Lipid Res. 35, 1634-1645.
  9. Ha, Y. C. and Barter, P. J. (1982) Differences in plasma cholesteryl ester transfer activity in sixteen vertebrate species. Comp. Biochem. Physiol. 71B, 265-269.
  10. Ha, Y. C., Chang, L. B. F. and Barter, P. J. (1985) Effects of injecting exogenous lipid transfer protein into rats. Biochim. Biophys. Acta 833, 205-210.
  11. Havel, R. J., Eder, H. A. and Bragdon, J. H. (1955) The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J. Clin. Invest. 34, 1345-1353. https://doi.org/10.1172/JCI103182
  12. Hayek, T., Chajek-Shaul, T., Walsh, A., Agellon, L. B., Moulin, P., Tall, A. R. and Breslow, J. L. (1992) An interaction between the human cholesteryl ester transfer protein (CETP) and apolipoprotein A-I genes in transgenic mice results in a profound CETP-mediated depression of high-density lipoprotein cholesterol levels, J. Clin. Invest. 90, 505-510. https://doi.org/10.1172/JCI115887
  13. Hesler, C. B., Swenson T. L. and Tall, A. R. (1987) Purification and characterization of human plasma cholesteryl ester transfer protein. J. Biol. Chem. 262, 2275-2282.
  14. Inazu, A., Brown, M. L., Hesler, C. B. Agellon, L. B., Koizumi, J., Takata, K., Maruhama, Y., Mabuchi, H. and Tall, A. R. (1990) Increased high density lipoprotein caused by a common cholesteryl ester transfer protein gene mutation. N. Engl. J. Med. 323, 1234-1238. https://doi.org/10.1056/NEJM199011013231803
  15. Jarnagin, A. S., Kohr, W. and Fielding, C. (1987) Isolation and specificity of a Mr 74,000 cholesteryl ester transfer protein from human plasma, Proc. Natl. Acad. Sci. USA 84, 1854-1857. https://doi.org/10.1073/pnas.84.7.1854
  16. Jiang, X., Moulin, P., Quinet, E., Goldberg, I. J., Yacoub, L. K., Agellon, L. B., Compton, D., Polokoff, R. and Tall, A. R. (1991) Mammalian adipose tissue and muscle are major sources of lipid transfer protein mRNA. J. Biol. Chem. 266, 4631-4639.
  17. Koizumi, J., Mabuchi, H., Yoshimura, A., Michishita, I., Takeda, M., Hoh, H., Sakai, Y., Sakai, T., Ueda, K. and Takeda, R. (1985) Deficiency of serum cholesteryl ester transfer activity in patients with familial hyperalphalipoproteineia. Atherosclerosis 58, 175-186. https://doi.org/10.1016/0021-9150(85)90064-4
  18. Lagrost, L., Gandjini, H., Athias, A., Guyard-Dangremont, V., Lallemant, C. and Gambert, P. (1993) Influence of plasma cholesteryl ester transfer activity on the LDL and HDL distribution profiles in nonnolipidemic subjects. Arterioscler. Thromb, 13, 815-825. https://doi.org/10.1161/01.ATV.13.6.815
  19. Marotti, K. R., Castle, C. K., Boyle, T. P., Lin, A. H., Murray, R. W. and Melchoir, G. W. (1993) Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature 364, 73-75. https://doi.org/10.1038/364073a0
  20. Marotti, K. R., Castle, C. K., Murray, R. W., Rehberg, E. F., Polites, H. G., and Melchoir, G. W. (1992) The role of cholesteryl ester transfer protein in primate apolipoprotein A-I metabolism: insights from studies with transgenic mice. Arterioscler. Thromb. 12, 736-744, https://doi.org/10.1161/01.ATV.12.6.736
  21. Nishina, P. M., Verstuyft, J. and Paigen, B. (1990) Synthetic low and high fat diets for the study of atherosclerosis in the mouse. J. Lipid Res. 31, 859-869.
  22. Noble, R. P. (1968) Electrophoretic separation of plasma lipoproteins in agarose gel. J. Lipid Res. 9, 693-700,
  23. Park, Y. B., Jeoung, N. H., Kim, H. S. and Choi, M. S. (1992) Reaction of HDL-bound CETP and a new method for its activity measurement. Korean Biochem. J. 25, 409-417,
  24. Quig, D. W. and Zilversmit, D. B. (1986) Disappearance and effects of exogenous lipid transfer activity in rats. Biochim, Biophys. Acta 879, 171-179. https://doi.org/10.1016/0005-2760(86)90100-1
  25. Sambrook, J., Fritsch, E. F. and Maniatis, T. (1989) Molecular cloning - a laboratory manual. 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York.
  26. Smith, P. K., Krohn, R. I., Hermanson, G. I., Mallia, A. K., Gartner, F. H., Provenzano, M. D., Fujimoto, E. K., Goeke, N. M., Olson, B. J. and Klenk, D. C. (1985) Measurement of protein using bicinchroninic acid. Anal. Biochem. 150, 76-85. https://doi.org/10.1016/0003-2697(85)90442-7
  27. Whitlock, M. E., Swenson, T. L., Ramakrishnan, R., Leonard, M, T., Marcel, Y. L., Milne, R. W. and Tall, A. R. (1989) Monoclonal antibody inhibition of cholesteryl ester transfer protein activity in the rabbit: effects on lipoprotein composition and cholesteryl ester metabolism. J. Clin. Invest. 84, 129-137. https://doi.org/10.1172/JCI114132

Cited by

  1. Cholesteryl ester transfer protein inhibitors as potential new therapies for coronary artery disease vol.16, pp.6, 2006, https://doi.org/10.1517/13543776.16.6.753