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. 1995 Oct;96(4):2071–2074. doi: 10.1172/JCI118255

Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene.

T Hayek 1, L Masucci-Magoulas 1, X Jiang 1, A Walsh 1, E Rubin 1, J L Breslow 1, A R Tall 1
PMCID: PMC185846  PMID: 7560101

Abstract

The human cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl ester from HDL to triglyceride-rich lipoproteins. The activity of CETP results in a reduction in HDL cholesterol levels, but CETP may also promote reverse cholesterol transport. Thus, the net impact of CETP expression on atherogenesis is uncertain. The influence of hypertriglyceridemia and CETP on the development of atherosclerotic lesions in the proximal aorta was assessed by feeding transgenic mice a high cholesterol diet for 16 wk. 13 out of 14 (93%) hypertriglyceridemic human apo CIII (HuCIII) transgenic (Tg) mice developed atherosclerotic lesions, compared to 18 out of 29 (62%) controls. In HuCIII/CETPTg, human apo AI/CIIITg and HuAI/CIII/CETPTg mice, 7 of 13 (54%), 5 of 10 (50%), and 5 of 13 (38%), respectively, developed lesions in the proximal aorta (P < .05 compared to HuCIIITg). The average number of aortic lesions per mouse in HuCIIITg and controls was 3.4 +/- 0.8 and 2.7 +/- 0.6, respectively in HuCIII/CETPTg, HuAI/CIIIg, and HuAI/CIII/CETPTg mice the number of lesions was significantly lower than in HuCIIITg and control mice: 0.9 +/- 0.4, 1.5 +/- 0.5, and 0.9 +/- 0.4, respectively. There were parallel reductions in mean lesion area. In a separate study, we found an increased susceptibility to dietary atherosclerosis in nonhypertriglyceridemic CETP transgenic mice compared to controls. We conclude that CETP expression inhibits the development of early atherosclerotic lesions but only in hypertriglyceridemic mice.

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Selected References

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  1. Aalto-Setälä K., Fisher E. A., Chen X., Chajek-Shaul T., Hayek T., Zechner R., Walsh A., Ramakrishnan R., Ginsberg H. N., Breslow J. L. Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles. J Clin Invest. 1992 Nov;90(5):1889–1900. doi: 10.1172/JCI116066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Agellon L. B., Walsh A., Hayek T., Moulin P., Jiang X. C., Shelanski S. A., Breslow J. L., Tall A. R. Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer protein transgenic mice. J Biol Chem. 1991 Jun 15;266(17):10796–10801. [PubMed] [Google Scholar]
  3. Albers J. J., Tollefson J. H., Chen C. H., Steinmetz A. Isolation and characterization of human plasma lipid transfer proteins. Arteriosclerosis. 1984 Jan-Feb;4(1):49–58. doi: 10.1161/01.atv.4.1.49. [DOI] [PubMed] [Google Scholar]
  4. Barter P. J., Hopkins G. J., Calvert G. D. Transfers and exchanges of esterified cholesterol between plasma lipoproteins. Biochem J. 1982 Oct 15;208(1):1–7. doi: 10.1042/bj2080001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Barter P., Rye K. A. Cholesteryl ester transfer protein: its role in plasma lipid transport. Clin Exp Pharmacol Physiol. 1994 Sep;21(9):663–672. doi: 10.1111/j.1440-1681.1994.tb02569.x. [DOI] [PubMed] [Google Scholar]
  6. Castelli W. P., Garrison R. J., Wilson P. W., Abbott R. D., Kalousdian S., Kannel W. B. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA. 1986 Nov 28;256(20):2835–2838. [PubMed] [Google Scholar]
  7. Chajek-Shaul T., Hayek T., Walsh A., Breslow J. L. Expression of the human apolipoprotein A-I gene in transgenic mice alters high density lipoprotein (HDL) particle size distribution and diminishes selective uptake of HDL cholesteryl esters. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6731–6735. doi: 10.1073/pnas.88.15.6731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Duane W. C. Abnormal bile acid absorption in familial hypertriglyceridemia. J Lipid Res. 1995 Jan;36(1):96–107. [PubMed] [Google Scholar]
  9. Einarsson K., Hellström K., Kallner M. Gallbladder disease in hyperlipoproteinaemia. Lancet. 1975 Mar 1;1(7905):484–487. doi: 10.1016/s0140-6736(75)92831-7. [DOI] [PubMed] [Google Scholar]
  10. Fielding C. J., Fielding P. E. Molecular physiology of reverse cholesterol transport. J Lipid Res. 1995 Feb;36(2):211–228. [PubMed] [Google Scholar]
  11. Fielding P. E., Fielding C. J., Havel R. J., Kane J. P., Tun P. Cholesterol net transport, esterification, and transfer in human hyperlipidemic plasma. J Clin Invest. 1983 Mar;71(3):449–460. doi: 10.1172/JCI110789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gordon D. J., Rifkind B. M. High-density lipoprotein--the clinical implications of recent studies. N Engl J Med. 1989 Nov 9;321(19):1311–1316. doi: 10.1056/NEJM198911093211907. [DOI] [PubMed] [Google Scholar]
  13. Hayek T., Azrolan N., Verdery R. B., Walsh A., Chajek-Shaul T., Agellon L. B., Tall A. R., Breslow J. L. Hypertriglyceridemia and cholesteryl ester transfer protein interact to dramatically alter high density lipoprotein levels, particle sizes, and metabolism. Studies in transgenic mice. J Clin Invest. 1993 Sep;92(3):1143–1152. doi: 10.1172/JCI116683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hayek T., Chajek-Shaul T., Walsh A., Agellon L. B., Moulin P., Tall A. R., Breslow J. L. 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. 1992 Aug;90(2):505–510. doi: 10.1172/JCI115887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Inazu A., Brown M. L., Hesler C. B., Agellon L. B., Koizumi J., Takata K., Maruhama Y., Mabuchi H., Tall A. R. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med. 1990 Nov 1;323(18):1234–1238. doi: 10.1056/NEJM199011013231803. [DOI] [PubMed] [Google Scholar]
  16. Ito Y., Azrolan N., O'Connell A., Walsh A., Breslow J. L. Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice. Science. 1990 Aug 17;249(4970):790–793. doi: 10.1126/science.2167514. [DOI] [PubMed] [Google Scholar]
  17. Jørgensen T. Gallstones and plasma lipids in a Danish population. Scand J Gastroenterol. 1989 Oct;24(8):916–922. doi: 10.3109/00365528909089235. [DOI] [PubMed] [Google Scholar]
  18. Lenfant C. NHLBI funding policies. Enhancing stability, predictability, and cost control. Circulation. 1994 Jul;90(1):1–1. doi: 10.1161/01.cir.90.1.1. [DOI] [PubMed] [Google Scholar]
  19. Marcel Y. L., McPherson R., Hogue M., Czarnecka H., Zawadzki Z., Weech P. K., Whitlock M. E., Tall A. R., Milne R. W. Distribution and concentration of cholesteryl ester transfer protein in plasma of normolipemic subjects. J Clin Invest. 1990 Jan;85(1):10–17. doi: 10.1172/JCI114397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Marotti K. R., Castle C. K., Boyle T. P., Lin A. H., Murray R. W., Melchior G. W. Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature. 1993 Jul 1;364(6432):73–75. doi: 10.1038/364073a0. [DOI] [PubMed] [Google Scholar]
  21. Miller N. E. Associations of high-density lipoprotein subclasses and apolipoproteins with ischemic heart disease and coronary atherosclerosis. Am Heart J. 1987 Feb;113(2 Pt 2):589–597. doi: 10.1016/0002-8703(87)90638-7. [DOI] [PubMed] [Google Scholar]
  22. Morton R. E., Zilversmit D. B. Inter-relationship of lipids transferred by the lipid-transfer protein isolated from human lipoprotein-deficient plasma. J Biol Chem. 1983 Oct 10;258(19):11751–11757. [PubMed] [Google Scholar]
  23. Paigen B., Morrow A., Holmes P. A., Mitchell D., Williams R. A. Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis. 1987 Dec;68(3):231–240. doi: 10.1016/0021-9150(87)90202-4. [DOI] [PubMed] [Google Scholar]
  24. Plump A. S., Scott C. J., Breslow J. L. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9607–9611. doi: 10.1073/pnas.91.20.9607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Plump A. S., Smith J. D., Hayek T., Aalto-Setälä K., Walsh A., Verstuyft J. G., Rubin E. M., Breslow J. L. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992 Oct 16;71(2):343–353. doi: 10.1016/0092-8674(92)90362-g. [DOI] [PubMed] [Google Scholar]
  26. Pászty C., Maeda N., Verstuyft J., Rubin E. M. Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice. J Clin Invest. 1994 Aug;94(2):899–903. doi: 10.1172/JCI117412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rubin E. M., Ishida B. Y., Clift S. M., Krauss R. M. Expression of human apolipoprotein A-I in transgenic mice results in reduced plasma levels of murine apolipoprotein A-I and the appearance of two new high density lipoprotein size subclasses. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):434–438. doi: 10.1073/pnas.88.2.434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rubin E. M., Krauss R. M., Spangler E. A., Verstuyft J. G., Clift S. M. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature. 1991 Sep 19;353(6341):265–267. doi: 10.1038/353265a0. [DOI] [PubMed] [Google Scholar]
  29. Tall A. R. Plasma lipid transfer proteins. J Lipid Res. 1986 Apr;27(4):361–367. [PubMed] [Google Scholar]
  30. Walsh A., Azrolan N., Wang K., Marcigliano A., O'Connell A., Breslow J. L. Intestinal expression of the human apoA-I gene in transgenic mice is controlled by a DNA region 3' to the gene in the promoter of the adjacent convergently transcribed apoC-III gene. J Lipid Res. 1993 Apr;34(4):617–623. [PubMed] [Google Scholar]
  31. Walsh A., Ito Y., Breslow J. L. High levels of human apolipoprotein A-I in transgenic mice result in increased plasma levels of small high density lipoprotein (HDL) particles comparable to human HDL3. J Biol Chem. 1989 Apr 15;264(11):6488–6494. [PubMed] [Google Scholar]

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