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Volume 272, Number 36, Issue of September 5, 1997 pp. 22685-22694
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Apolipoprotein E2 Transgenic Rabbits
MODULATION OF THE TYPE III HYPERLIPOPROTEINEMIC PHENOTYPE BY ESTROGEN AND OCCURRENCE OF SPONTANEOUS ATHEROSCLEROSIS

(Received for publication, March 12, 1997, and in revised form, June 9, 1997)

Yadong Huang ^§ , Susan W. Schwendner , Stanley C. Rall Jr. , David A. Sanan ^§ and Robert W. Mahley ^§¶

From the  Gladstone Institute of Cardiovascular Disease, ^§ Cardiovascular Research Institute, and the Departments of ^¶ Pathology and Medicine, University of California, San Francisco, California 94141-9100

Transgenic rabbits were produced that expressed high plasma levels (30-70 mg/dl) of human apolipoprotein (apo) E2(Cys-158), an apoE variant associated with the human genetic disorder type III hyperlipoproteinemia (HLP). Male transgenic rabbits fed normal chow had up to 8-fold (289 ± 148 mg/dl) and 15-fold (697 ± 452 mg/dl) increases in plasma total cholesterol and triglycerides, respectively, compared with nontransgenic males. Female transgenic rabbits had only a modest hyperlipidemia (total cholesterol, 140 ± 46 mg/dl; total triglycerides, 174 ± 66 mg/dl). Both sexes displayed the hallmarks of type III HLP: -migrating very low density lipoproteins (-VLDL) (intestinal and hepatic remnant lipoproteins) and significantly increased VLDL and intermediate density lipoproteins. Apolipoprotein E2-containing VLDL particles were cleared from the circulation more slowly and were more resistant to lipoprotein lipase-mediated lipolysis than normal VLDL. Only females had increased high density lipoproteins (HDL) (40%), which were shifted from typical small HDL to larger HDL₁. Plasma apoE2 was predominantly associated with -VLDL in males and with HDL in females. To ascertain reasons for the phenotypic gender difference, we treated the male transgenic rabbits with 17-ethinyl estradiol. Estrogen treatment for 10 days dramatically decreased total cholesterol (73%) and triglycerides (89%) and converted -VLDL to pre--migrating VLDL. Concomitantly, lipoprotein lipase and hepatic lipase activities increased by 90%, low density lipoprotein receptor activity was stimulated significantly, apoE2 was redistributed to HDL, and HDL were converted to HDL₁. Conversely, ovariectomy in female transgenic rabbits significantly increased total cholesterol (75%), triglycerides (117%), and -VLDL, while decreasing lipoprotein lipase and hepatic lipase activities by 35% and redistributing apoE2 to the -VLDL. Thus, estrogen status appears to be responsible for much of the gender difference of the lipoprotein phenotype, mainly by modulating both lipase and low density lipoprotein receptor activities. Furthermore, transgenic rabbits fed normal chow for 11 months developed fatty streaks, and some had more advanced atherosclerotic lesions, especially around the aortic arch and proximal abdominal aorta. The lesions were more extensive in males, roughly correlating with the magnitude of the hyperlipidemia. Therefore, high plasma levels of human apoE2 in transgenic rabbits result in a type III HLP phenotype, in which males have both more severe hyperlipidemia and more extensive atherosclerosis than females.

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