This Article Full Text Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fan, J. Articles by Young, S. G. Search for Related Content PubMed PubMed Citation Articles by Fan, J. Articles by Young, S. G.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1889-1899.)
© 1995 American Heart Association, Inc.

Articles

Overexpression of Human Apolipoprotein B-100 in Transgenic Rabbits Results in Increased Levels of LDL and Decreased Levels of HDL

Jianglin Fan; Sally P.A. McCormick; Ronald M. Krauss; Stacy Taylor; Ricky Quan; John M. Taylor; Stephen G. Young

From the Gladstone Institute of Cardiovascular Disease (J.F., S.P.A.M., S.T., R.Q., J.M.T., S.G.Y.), San Francisco; the Cardiovascular Research Institute (J.F., S.P.A.M., J.M.T., S.G.Y.), University of California, San Francisco; the Lawrence Berkeley Laboratory (R.M.K.), University of California, Berkeley; and the Departments of Physiology (J.M.T.) and Medicine (S.G.Y.), University of California, San Francisco.

Correspondence to Stephen G. Young, MD, and John M. Taylor, PhD, Gladstone Institute of Cardiovascular Disease, PO Box 419100, San Francisco, CA 94141-9100.

Abstract In this study, an 80-kb human genomic DNA fragment spanning the human apoB gene was used to generate transgenic New Zealand White rabbits that expressed human apoB-100. The concentration of human apoB in the plasma of the transgenic rabbits ranged between 5 and 100 mg/dL. The transgenic rabbits had nearly threefold elevations in the plasma levels of triglycerides and cholesterol compared with nontransgenic controls. Nearly all the cholesterol and human apoB in the plasma was in the LDL fraction. Pronounced triglyceride enrichment of the LDL fraction was a striking feature of human apoB overexpression in the transgenic rabbits, in which the LDL fraction contained more than 75% of the plasma triglycerides. The triglyceride-enriched LDL particles were smaller and more dense than the native rabbit LDL and contained markedly increased amounts of apoE and apoC-III. In the nontransgenic control animals most of the triglycerides were in the VLDL, and most of the apoE and apoC-III were in the VLDL and HDL fractions. In addition to increased LDL levels, overexpression of human apoB in rabbits resulted in lower plasma levels of HDL cholesterol and apoA-I. In our prior studies on transgenic mice expressing human apoB, we documented triglyceride-rich LDL and reduced levels of HDL cholesterol. These prior findings in mice, together with the present findings in transgenic rabbits, suggest that triglyceride-rich LDL and lowered levels of HDL cholesterol may be hallmark features of apoB overexpression.

Key Words: cholesterol • apolipoprotein B • transgenic rabbits

This article has been cited by other articles:

				M. Rizzo, J. M. Taylor, C. M. Barbagallo, K. Berneis, P. J. Blanche, and R. M. Krauss Effects on Lipoprotein Subclasses of Combined Expression of Human Hepatic Lipase and Human apoB in Transgenic Rabbits Arterioscler Thromb Vasc Biol, January 1, 2004; 24(1): 141 - 146. [Abstract] [Full Text] [PDF]

				P. Kee, K.-A. Rye, J. L. Taylor, P. H. R. Barrett, and P. J. Barter Metabolism of ApoA-I as Lipid-Free Protein or as Component of Discoidal and Spherical Reconstituted HDLs: Studies in Wild-Type and Hepatic Lipase Transgenic Rabbits Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1912 - 1917. [Abstract] [Full Text] [PDF]

				K. Singh, O. A. Batuman, H. O. Akman, M. H. Kedees, V. Vakil, and M. M. Hussain Differential, Tissue-specific, Transcriptional Regulation of Apolipoprotein B Secretion by Transforming Growth Factor beta J. Biol. Chem., October 11, 2002; 277(42): 39515 - 39524. [Abstract] [Full Text] [PDF]

				K. K. Berneis and R. M. Krauss Metabolic origins and clinical significance of LDL heterogeneity J. Lipid Res., September 1, 2002; 43(9): 1363 - 1379. [Abstract] [Full Text] [PDF]

				J. Fan, M. Challah, H. Shimoyamada, M. Shiomi, S. Marcovina, and T. Watanabe Defects of the LDL receptor in WHHL transgenic rabbits lead to a marked accumulation of plasma lipoprotein[a] J. Lipid Res., June 1, 2000; 41(6): 1004 - 1012. [Abstract] [Full Text]

				H. A. Ardern, G. M. Benson, K. E. Suckling, M. J. Caslake, J. Shepherd, and C. J. Packard Apolipoprotein B overproduction by the perfused liver of the St. Thomas' mixed hyperlipidemic (SMHL) rabbit J. Lipid Res., December 1, 1999; 40(12): 2234 - 2243. [Abstract] [Full Text] [PDF]

				F. M. van 't Hooft, S. Jormsjö, B. Lundahl, P. Tornvall, P. Eriksson, and A. Hamsten A functional polymorphism in the apolipoprotein B promoter that influences the level of plasma low density lipoprotein J. Lipid Res., September 1, 1999; 40(9): 1686 - 1694. [Abstract] [Full Text]

				M. E. Brousseau and J. M. Hoeg Transgenic rabbits as models for atherosclerosis research J. Lipid Res., March 1, 1999; 40(3): 365 - 375. [Abstract] [Full Text]

				R. L. Hamilton, J. S. Wong, C. M. Cham, L. B. Nielsen, and S. G. Young Chylomicron-sized lipid particles are formed in the setting of apolipoprotein B deficiency J. Lipid Res., August 1, 1998; 39(8): 1543 - 1557. [Abstract] [Full Text]

				B. Lamarche, K. D. Uffelman, G. Steiner, P. H. R. Barrett, and G. F. Lewis Analysis of particle size and lipid composition as determinants of the metabolic clearance of human high density lipoproteins in a rabbit model J. Lipid Res., June 1, 1998; 39(6): 1162 - 1172. [Abstract] [Full Text]

				D. A. Sanan, D. L. Newland, R. Tao, S. Marcovina, J. Wang, V. Mooser, R. E. Hammer, and H. H. Hobbs Low density lipoprotein receptor-negative mice expressing human apolipoprotein B-100 develop complex atherosclerotic lesions on a chow diet: No accentuation by apolipoprotein(a) PNAS, April 14, 1998; 95(8): 4544 - 4549. [Abstract] [Full Text] [PDF]

				E. Kim and S. G. Young Genetically modified mice for the study of apolipoprotein B J. Lipid Res., April 1, 1998; 39(4): 703 - 723. [Abstract] [Full Text] [PDF]

				D. Rouy, N. Duverger, S. D. Lin, F. Emmanuel, L.-M. Houdebine, P. Denefle, C. Viglietta, E. Gong, E. M. Rubin, and S. D. Hughes Apolipoprotein(a) Yeast Artificial Chromosome Transgenic Rabbits. LIPOPROTEIN(a) ASSEMBLY WITH HUMAN AND RABBIT APOLIPOPROTEIN B J. Biol. Chem., January 9, 1998; 273(2): 1247 - 1251. [Abstract] [Full Text] [PDF]

				L. B. Nielsen, S. P. A. McCormick, V. Pierotti, C. Tam, M. D. Gunn, H. Shizuya, and S. G. Young Human Apolipoprotein B Transgenic Mice Generated with 207- and 145-Kilobase Pair Bacterial Artificial Chromosomes. EVIDENCE THAT A DISTANT 5'-ELEMENT CONFERS APPROPRIATE TRANSGENE EXPRESSION IN THE INTESTINE J. Biol. Chem., November 21, 1997; 272(47): 29752 - 29758. [Abstract] [Full Text] [PDF]

				Y. Huang, S. W. Schwendner, S. C. Rall Jr., D. A. Sanan, and R. W. Mahley Apolipoprotein E2 Transgenic Rabbits. MODULATION OF THE TYPE III HYPERLIPOPROTEINEMIC PHENOTYPE BY ESTROGEN AND OCCURRENCE OF SPONTANEOUS ATHEROSCLEROSIS J. Biol. Chem., September 5, 1997; 272(36): 22685 - 22694. [Abstract] [Full Text] [PDF]

				S. P. A. McCormick, J. K. Ng, M. Véniant, J. Borén, V. Pierotti, L. M. Flynn, D. S. Grass, A. Connolly, and S. G. Young Transgenic Mice That Overexpress Mouse Apolipoprotein B J. Biol. Chem., May 17, 1996; 271(20): 11963 - 11970. [Abstract] [Full Text] [PDF]