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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 Sep 15;90(18):8314–8318. doi: 10.1073/pnas.90.18.8314

Transgenic mouse models of lipoprotein metabolism and atherosclerosis.

J L Breslow 1
PMCID: PMC47346  PMID: 8378301

Abstract

Lipoprotein transport genes have either been added to the germ line of mice by transgenic techniques or knocked out by homologous recombination in embryonic stem cells. The resultant over- or underexpression of these genes has resulted in new insights about how these genes function in the body and their role in lipoprotein metabolism. Either singly or in combination, these genetic modifications can be used to engineer the mouse to make it a better model for human lipoprotein disorders and atherosclerosis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  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. Breslow J. L. Lipoprotein transport gene abnormalities underlying coronary heart disease susceptibility. Annu Rev Med. 1991;42:357–371. doi: 10.1146/annurev.me.42.020191.002041. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Chiesa G., Hobbs H. H., Koschinsky M. L., Lawn R. M., Maika S. D., Hammer R. E. Reconstitution of lipoprotein(a) by infusion of human low density lipoprotein into transgenic mice expressing human apolipoprotein(a). J Biol Chem. 1992 Dec 5;267(34):24369–24374. [PubMed] [Google Scholar]
  6. Dammerman M., Sandkuijl L. A., Halaas J. L., Chung W., Breslow J. L. An apolipoprotein CIII haplotype protective against hypertriglyceridemia is specified by promoter and 3' untranslated region polymorphisms. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4562–4566. doi: 10.1073/pnas.90.10.4562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Hayek T., Chajek-Shaul T., Walsh A., Azrolan N., Breslow J. L. Probucol decreases apolipoprotein A-I transport rate and increases high density lipoprotein cholesteryl ester fractional catabolic rate in control and human apolipoprotein A-I transgenic mice. Arterioscler Thromb. 1991 Sep-Oct;11(5):1295–1302. doi: 10.1161/01.atv.11.5.1295. [DOI] [PubMed] [Google Scholar]
  9. Hayek T., Ito Y., Azrolan N., Verdery R. B., Aalto-Setälä K., Walsh A., Breslow J. L. Dietary fat increases high density lipoprotein (HDL) levels both by increasing the transport rates and decreasing the fractional catabolic rates of HDL cholesterol ester and apolipoprotein (Apo) A-I. Presentation of a new animal model and mechanistic studies in human Apo A-I transgenic and control mice. J Clin Invest. 1993 Apr;91(4):1665–1671. doi: 10.1172/JCI116375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hayek T., Ito Y., Azrolan N., Verdery R. B., Aalto-Setälä K., Walsh A., Breslow J. L. Dietary fat increases high density lipoprotein (HDL) levels both by increasing the transport rates and decreasing the fractional catabolic rates of HDL cholesterol ester and apolipoprotein (Apo) A-I. Presentation of a new animal model and mechanistic studies in human Apo A-I transgenic and control mice. J Clin Invest. 1993 Apr;91(4):1665–1671. doi: 10.1172/JCI116375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Herz J., Clouthier D. E., Hammer R. E. LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation. Cell. 1992 Oct 30;71(3):411–421. doi: 10.1016/0092-8674(92)90511-a. [DOI] [PubMed] [Google Scholar]
  12. Hofmann S. L., Russell D. W., Brown M. S., Goldstein J. L., Hammer R. E. Overexpression of low density lipoprotein (LDL) receptor eliminates LDL from plasma in transgenic mice. Science. 1988 Mar 11;239(4845):1277–1281. doi: 10.1126/science.3344433. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Jiang X. C., Agellon L. B., Walsh A., Breslow J. L., Tall A. Dietary cholesterol increases transcription of the human cholesteryl ester transfer protein gene in transgenic mice. Dependence on natural flanking sequences. J Clin Invest. 1992 Oct;90(4):1290–1295. doi: 10.1172/JCI115993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lawn R. M., Wade D. P., Hammer R. E., Chiesa G., Verstuyft J. G., Rubin E. M. Atherogenesis in transgenic mice expressing human apolipoprotein(a) Nature. 1992 Dec 17;360(6405):670–672. doi: 10.1038/360670a0. [DOI] [PubMed] [Google Scholar]
  16. Marotti K. R., Castle C. K., Murray R. W., Rehberg E. F., Polites H. G., Melchior G. W. The role of cholesteryl ester transfer protein in primate apolipoprotein A-I metabolism. Insights from studies with transgenic mice. Arterioscler Thromb. 1992 Jun;12(6):736–744. doi: 10.1161/01.atv.12.6.736. [DOI] [PubMed] [Google Scholar]
  17. Paigen B., Mitchell D., Reue K., Morrow A., Lusis A. J., LeBoeuf R. C. Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3763–3767. doi: 10.1073/pnas.84.11.3763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pathak R. K., Yokode M., Hammer R. E., Hofmann S. L., Brown M. S., Goldstein J. L., Anderson R. G. Tissue-specific sorting of the human LDL receptor in polarized epithelia of transgenic mice. J Cell Biol. 1990 Aug;111(2):347–359. doi: 10.1083/jcb.111.2.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Piedrahita J. A., Zhang S. H., Hagaman J. R., Oliver P. M., Maeda N. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4471–4475. doi: 10.1073/pnas.89.10.4471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. 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]
  22. 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]
  23. Schultz J. R., Gong E. L., McCall M. R., Nichols A. V., Clift S. M., Rubin E. M. Expression of human apolipoprotein A-II and its effect on high density lipoproteins in transgenic mice. J Biol Chem. 1992 Oct 25;267(30):21630–21636. [PubMed] [Google Scholar]
  24. Shimano H., Yamada N., Katsuki M., Shimada M., Gotoda T., Harada K., Murase T., Fukazawa C., Takaku F., Yazaki Y. Overexpression of apolipoprotein E in transgenic mice: marked reduction in plasma lipoproteins except high density lipoprotein and resistance against diet-induced hypercholesterolemia. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1750–1754. doi: 10.1073/pnas.89.5.1750. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Shimano H., Yamada N., Katsuki M., Yamamoto K., Gotoda T., Harada K., Shimada M., Yazaki Y. Plasma lipoprotein metabolism in transgenic mice overexpressing apolipoprotein E. Accelerated clearance of lipoproteins containing apolipoprotein B. J Clin Invest. 1992 Nov;90(5):2084–2091. doi: 10.1172/JCI116091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Simonet W. S., Bucay N., Lauer S. J., Taylor J. M. A far-downstream hepatocyte-specific control region directs expression of the linked human apolipoprotein E and C-I genes in transgenic mice. J Biol Chem. 1993 Apr 15;268(11):8221–8229. [PubMed] [Google Scholar]
  27. Simonet W. S., Bucay N., Lauer S. J., Wirak D. O., Stevens M. E., Weisgraber K. H., Pitas R. E., Taylor J. M. In the absence of a downstream element, the apolipoprotein E gene is expressed at high levels in kidneys of transgenic mice. J Biol Chem. 1990 Jul 5;265(19):10809–10812. [PubMed] [Google Scholar]
  28. Simonet W. S., Bucay N., Pitas R. E., Lauer S. J., Taylor J. M. Multiple tissue-specific elements control the apolipoprotein E/C-I gene locus in transgenic mice. J Biol Chem. 1991 May 15;266(14):8651–8654. [PubMed] [Google Scholar]
  29. Smith J. D., Plump A. S., Hayek T., Walsh A., Breslow J. L. Accumulation of human apolipoprotein E in the plasma of transgenic mice. J Biol Chem. 1990 Sep 5;265(25):14709–14712. [PubMed] [Google Scholar]
  30. Swanson M. E., Hughes T. E., Denny I. S., France D. S., Paterniti J. R., Jr, Tapparelli C., Gfeller P., Bürki K. High level expression of human apolipoprotein A-I in transgenic rats raises total serum high density lipoprotein cholesterol and lowers rat apolipoprotein A-I. Transgenic Res. 1992 May;1(3):142–147. doi: 10.1007/BF02528779. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. 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]
  33. Williamson R., Lee D., Hagaman J., Maeda N. Marked reduction of high density lipoprotein cholesterol in mice genetically modified to lack apolipoprotein A-I. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):7134–7138. doi: 10.1073/pnas.89.15.7134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Yokode M., Hammer R. E., Ishibashi S., Brown M. S., Goldstein J. L. Diet-induced hypercholesterolemia in mice: prevention by overexpression of LDL receptors. Science. 1990 Nov 30;250(4985):1273–1275. doi: 10.1126/science.2244210. [DOI] [PubMed] [Google Scholar]
  35. Zhang S. H., Reddick R. L., Piedrahita J. A., Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992 Oct 16;258(5081):468–471. doi: 10.1126/science.1411543. [DOI] [PubMed] [Google Scholar]
  36. van den Maagdenberg A. M., Hofker M. H., Krimpenfort P. J., de Bruijn I., van Vlijmen B., van der Boom H., Havekes L. M., Frants R. R. Transgenic mice carrying the apolipoprotein E3-Leiden gene exhibit hyperlipoproteinemia. J Biol Chem. 1993 May 15;268(14):10540–10545. [PubMed] [Google Scholar]

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