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Cytotechnology

, Volume 33, Issue 1–3, pp 93–99 | Cite as

Transgenic rabbits expressing human lipoprotein lipase

  • Masahiro Araki
  • Jianglin FanEmail author
  • Mireille Challah
  • André Bensadoun
  • Nobuhiro Yamada
  • Kazuo Honda
  • Teruo Watanabe
Article

Abstract

To study the functions of lipoprotein lipase (LPL) in lipid and lipoprotein metabolism and the relationship between LPL and atherosclerosis, we generated transgenic rabbits expressing the human LPL gene. A total of 4045 Japanese whiterabbit embryos were microinjected with a 3.8-kb SalI/HindIII fragment containing the chicken β-actin promoter, human LPL cDNA and rabbit β-globin with poly (A) signals, and then transplanted into 116 recipient rabbits. Of the 166 pups born, six pups were transgenic as confirmed by Southern blot analysis. ANorthern blot analysis revealed that human LPL was expressed by a number of tissues including the heart, kidney, adrenal gland and intestine. One transgenic rabbit showed up to 3-foldincreased LPL activity in post-heparin plasma compared to thatin nontransgenic rabbits. Human LPL expression in various tissues of transgenic rabbits was further elucidated by in situ hybridization and immunostaining. Since rabbits are superior to mice as a model of atherosclerosis, this transgenicrabbit model should provide a valuable tool for the study of LPL in lipid metabolism and atherosclerosis.

atherosclerosis lipoprotein lipoprotein lipase transgenic rabbit 

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References

  1. Araki M, Fan J and Watanabe T (1998) Immunohistochemical localization of lipoprotein lipase and apolipoprotein E in human atherosclerotic lesions. Acta Histochem Cytochem 31: 485–492.Google Scholar
  2. Bensadoun A, Ehnholm C, Steinberg D and Brown W (1974) Purification and characterization of lipoprotein lipase from pig adipose tissue. J Biol Chem 249: 2220–2227.Google Scholar
  3. Camps L, Reina M, Llobera M, Vilaro S and Olivecrona T (1990) Lipoprotein lipase: cellular origin and functional distribution. Am J Physiol 258: C673–C681.Google Scholar
  4. Challah M, Nicoletti A, Arnal J, Philippe M, Laboulandine I, Allegrini J, Alhenc-Gelas F, Danilov S and Michel J (1995) Cardiac angiotensin converting enzyme overproduction indicates interstitial activation in renovascular hypertension. Cardiovasc Res 30: 231–239.Google Scholar
  5. Duverger N, Viglietta C, Berthou L, Emmanuel F, Tailleux A, Parmentier-Nihoul L, Laine B, Fievet C, Castro G, Fruchart J, Houbebine L and Denèle P (1996) Transgenic rabbits expressing human apolipoprotein A-I in the liver. Arterioscler Thromb Vasc Biol 16: 1424–1429.Google Scholar
  6. Eckel R (1989) Lipoprotein lipase. A multifunctional enzyme relevant to common metabolic disease. New Eng J Med 320: 1060-1068.Google Scholar
  7. Fan J, Wang J, Bensadoun A, Lauer S, Dang Q, Mahley R and Taylor J (1994) Overexpression of hepatic lipase in transgenic rabbits leads to a marked reduction of plasma high density lipoproteins and intermediate density lipoproteins. Proc Natl Acad Sci USA 91: 8724–8728.Google Scholar
  8. Fan J, McCormick S, Krauss R, Taylor S, Quan R, Taylor J and Young S (1995) Overexpression of human apolipoprotein B-100 in transgenic rabbits results in increased levels of LDL and decreased levels of HDL. Arterioscler Thromb Vasc Biol 15: 1889–1899.Google Scholar
  9. Fan J, Ji Z, Huang Y, de Silva H, Sanan D, Mahley R, Innerarity T and Taylor J (1998) Increased expression of apolipoprotein E in transgenic rabbits results in reduced levels of very low density lipoproteins and an accumulation of low density lipoproteins in plasma. J Clin Invest 101: 2151–2164.Google Scholar
  10. Hammer R, Pursel V, Rexroad Jr C, Wall R, Bolt D, Ebert K, Palmiter R and Brinster R (1985) Production of transgenic rabbits, sheep and pigs by microinjection. Nature 315: 680–683.Google Scholar
  11. Hoeg J, Vaisman B, Demosky S, Meyn S, Talley G, Hoyt R, Feldman S, Béard A, Sakai N, Wood D, Brousseau M, Marcovina S, Brewer H and Santamarina-Fojo S (1996) Lecithin:cholesterol acyltransferase overexpression generates hyperalpha-lipoproteinemia and a nonatherogenic lipoprotein pattern in transgenic rabbits. J Biol Chem 271: 4396–4402.Google Scholar
  12. Jensen D, Schlaepfer I, Morin C, Pennington D, Marcell T, Ammon S, Gutierrez-Hartmann A and Eckel R (1997) Prevention of diet-induced obesity in transgenic mice overexpressing skeletal muscle lipoprotein lipase Am J Physiol 273: R683–R689.Google Scholar
  13. Jonasson L, Bondjers G and Hansson G (1987) Lipoprotein lipase in atherosclerosis: its presence in smooth muscle cells and absence from macrophages J Lipid Res 28: 437–445.Google Scholar
  14. Levak-Frank S, Radner H, Walsh A, Stollberger R, Knipping G, Hoefler G, Sattler W, Weinstock P, Breslow J and Zechner R (1995) Muscle-specific overexpression of lipoprotein lipase causes a severe myopathy characterized by proliferation of mitochondria and peroxisomes in transgenic mice. J Clin Invest 96: 976–986.Google Scholar
  15. Lindqvist P, Ostlund-Lindqvist A, Witztum J, Steinberg D and Little J (1983) The role of lipoprotein lipase in the metabolism of triglyceride-rich lipoproteins by macrophages. J Biol Chem 258: 9086–9092.Google Scholar
  16. Lindsey J and Fox R (1994) Inherited disease and variations. In: Manning P, Ringler D and Newcomer C (eds) The Biology of The Laboratory Rabbit (pp. 293–319). Academic Press, San Diego, CA.Google Scholar
  17. Liu M, Jirik F, LeBoeuf R, Henderson H, Castellani L, Lusis A, Ma Y, Forsythe I, Zhang H, Kirk E, Brunzell J and Hayden M (1994) Alteration of lipid profiles in plasma of transgenic mice expressing human lipoprotein lipase. J Biol Chem 269: 11417–11424.Google Scholar
  18. Mattsson L, Johansson H, Ottosson M, Bondjers G and Wiklund O (1993) Expression of lipoprotein lipase mRNA and secretion in macrophages isolated from human atherosclerotic aorta. J Clin Invest 92: 1759–1765.Google Scholar
  19. Niwa H, Yamamura K and Miyazaki J (1991) Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108: 193–200.Google Scholar
  20. O'Brien K, Gordon D, Deeb S, Ferguson M and Chait A (1992) Lipoprotein lipase is synthesized by macrophage-derived foam cells in human coronary atherosclerotic plaques. J Clin Invest 89: 1544–1550.Google Scholar
  21. Shimada M, Shimano H, Gotoda T, Yamamoto K, Kawamura M, Inaba T, Yazaki Y and Yamada N (1993) Overexpression of human lipoprotein lipase in transgenic mice. J Biol Chem 268: 17924–17929.Google Scholar
  22. Shimada M, Ishibashi S, Inaba T, Yagyu H, Harada K, Osuga J, Ohashi K, Yazaki Y and Yamada N (1996) Suppression of diet-induced atherosclerosis in low density lipoprotein receptor knockout mice overexpressing lipoprotein lipase. Proc Natl Acad Sci USA 93: 7242–7246.Google Scholar
  23. Taylor J and Fan J (1997) Transgenic rabbit models for the study of atherosclerosis. Frontiers in Bioscience 2: d298–308.Google Scholar
  24. Williams K and Tabas I (1995) The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol 15: 551–561.Google Scholar
  25. Wion K, Kirchgessner T, Lusis A, Shotz M and Lawn R (1987) Human lipoprotein lipase complementary DNA sequence. Science 235: 1638–1641.Google Scholar
  26. Yamanaka S, Balestra M, Ferrell L, Fan J, Arnold K, Taylor S, Taylor J and Innerarity T (1995) Apolipoprotein B mRNA-editing protein induces hepatocellular carcinoma and dysplasia in transgenic animals. Proc Natl Acad Sci USA 92: 8483–8487.Google Scholar
  27. Ylä-Herttuala S, Lipton B, Rosenfeld M, Goldberg I, Steinberg D and Witztum J (1991) Macrophages and smooth muscle cells express lipoprotein lipase in human and rabbit atherosclerotic lesions. Proc Natl Acad Sci USA 88: 10143–10147.Google Scholar
  28. Zilversmit D (1973) A proposal linking atherogenesis to the interaction of endothelial lipoprotein lipase with triglyceride-rich lipoproteins Circ Res 33: 633–638.Google Scholar
  29. Zsigmond E, Scheffler E, Forte T, Potenz R, Wu W and Chan L (1994) Transgenic mice expressing human lipoprotein lipase driven by the mouse metallothionein promoter. J Biol Chem 269: 18757–18766.Google Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Masahiro Araki
    • 1
  • Jianglin Fan
    • 2
    Email author
  • Mireille Challah
    • 1
  • André Bensadoun
    • 3
  • Nobuhiro Yamada
    • 4
  • Kazuo Honda
    • 5
  • Teruo Watanabe
    • 1
  1. 1.Department of Pathology, Institute of Basic Medical SciencesUniversity of TsukubaTsukubaJapan
  2. 2.Department of Pathology, Institute of Basic Medical SciencesUniversity of TsukubaTsukubaJapan
  3. 3.Division of NutritionCornell UniversityIthacaU.S.A.
  4. 4.Third Department of Internal MedicineUniversity of TokyoTokyoJapan
  5. 5.Tsukuba Research Center of Yamanouchi Pharmaceutical Company LimitedTsukubaJapan

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