|[Frontiers in Bioscience 2, d298-308, June 15, 1997]|
TRANSGENIC RABBIT MODELS FOR THE STUDY OF ATHEROSCLEROSIS
John M. Taylor and Jianglin Fan
Gladstone Institute of Cardiovascular Disease, the Department of Physiology, and the Cardiovascular Research Institute, University of California, San Francisco, CA
A human LCAT gene construct was used to generate transgenic rabbits that expressed the transgene at high levels in the liver and lower levels in the brain (57, 58). Three founders were identified, one of which had a high transgene integration copy number and a 16-fold increase in plasma levels of LCAT activity over nontransgenic control animals. The total and HDL cholesterol levels were increased fourfold and sevenfold, respectively, in the transgenic rabbits, indicating that LCAT activity plays a direct regulatory role in determining the HDL content of plasma. These changes were associated with an accumulation of cholesteryl ester-rich apoE-enriched HDL1 and a large reduction in VLDL content.
Supplementing the diet with 0.3% cholesterol for 17 weeks resulted in a 20% increase in HDL cholesterol (59). The non-HDL cholesterol in plasma was increased to ~500 mg/dl in nontransgenic controls but to only ~200 mg/dl in the LCAT transgenic rabbits. These changes were associated with a marked protection against atherosclerosis: the arterial surfaces of control rabbits had a 35% lesion area (~550 mg/dl total cholesterol) , whereas the transgenic rabbits had only a 5% lesion area (~400 mg/dl cholesterol). These studies demonstrated the involvement of LCAT in the metabolism of both HDL and apoB-containing lipoproteins.