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Transgenic rabbits expressing human apolipoprotein A-I in the liver
N Duverger1, C Viglietta, L Berthou
1Rhône-Poulenc Rorer-Gencell, Atherosclerosis Department, Centre de recherche de Vitry-Alfortville, Vitry sur Seine, France. nicolas.duverger@rp.fr
Arteriosclerosis, Thrombosis, and Vascular Biology
|December 1, 1996
Summary
Transgenic rabbits expressing human apolipoprotein A-I (apo A-I) showed reduced atherosclerosis risk. Increased apo A-I levels correlated with higher HDL cholesterol and improved lipoprotein profiles, indicating a potential therapeutic target.
Area of Science:
- Cardiovascular Biology
- Genetics and Transgenics
- Lipid Metabolism
Background:
- Apolipoprotein A-I (apo A-I) is the primary protein component of high-density lipoprotein (HDL) and plays a crucial role in reverse cholesterol transport.
- Dysregulation of apo A-I levels is implicated in the development of atherosclerosis.
- Developing animal models that mimic human lipid metabolism is essential for studying atherosclerosis.
Purpose of the Study:
- To create and characterize transgenic rabbits expressing human apolipoprotein A-I (apo A-I).
- To evaluate the impact of increased hepatic apo A-I expression on plasma lipoprotein profiles and cholesterol metabolism.
- To assess the utility of these transgenic rabbits as a model for atherosclerosis research.
Main Methods:
- Generation of transgenic rabbits using an 11-kb genomic human apo A-I construct with a liver-specific promoter.
- Analysis of plasma human apo A-I and rabbit apo A-I levels in founder and progeny generations.
- Quantification of HDL cholesterol (HDL-C), VLDL+LDL-C, and assessment of lipoprotein composition and size.
- Evaluation of cell cholesterol efflux using serum from transgenic and control rabbits.
Main Results:
- Five independent transgenic rabbit lines expressing human apo A-I were established.
- Plasma human apo A-I levels varied significantly, with substantial decreases in rabbit apo A-I.
- Two lines exhibited significantly higher HDL-C levels and less atherogenic lipoprotein profiles.
- Cell cholesterol efflux was positively correlated with HDL cholesterol, apo A-I levels, and pre-beta apo A-I-containing lipoproteins.
Conclusions:
- Transgenic rabbits with increased hepatic apo A-I expression demonstrate a promising model for studying atherosclerosis.
- Elevated human apo A-I levels lead to improved lipoprotein profiles and enhanced cholesterol efflux.
- These findings support the potential of targeting apo A-I for cardiovascular disease prevention.