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Type III hyperlipoproteinemic phenotype in transgenic mice expressing dysfunctional apolipoprotein E
1Gladstone Institute of Cardiovascular Disease, University of California, San Francisco 94141-9100.
The Journal of Clinical Investigation
|September 1, 1993
Summary
Transgenic mice expressing a dysfunctional apo E variant developed severe hyperlipidemia and beta-very low density lipoproteins (beta-VLDL), mimicking human type III hyperlipoproteinemia (HLP). These mice serve as a valuable animal model for studying this genetic lipid disorder.
Area of Science:
- Genetics
- Molecular Biology
- Cardiovascular Science
Background:
- Type III hyperlipoproteinemia (HLP) is a genetic disorder characterized by elevated cholesterol and triglycerides.
- Apo E variants, such as apo E (Arg-112, Cys-142), are associated with dominant inheritance of type III HLP.
- Understanding the molecular mechanisms of apo E dysfunction is crucial for developing therapeutic strategies.
Purpose of the Study:
- To create and characterize a transgenic mouse model expressing a human apo E variant linked to type III HLP.
- To investigate the in vivo effects of this dysfunctional apo E variant on plasma lipid levels and lipoprotein metabolism.
- To assess the suitability of this mouse model for studying the pathogenesis of type III HLP.
Main Methods:
- Generation of transgenic mice expressing the human apo E (Arg-112, Cys-142) variant.
- Quantification of plasma apo E, cholesterol, and triglyceride levels.
- Analysis of plasma lipoproteins using agarose electrophoresis.
- Assessment of beta-very low density lipoprotein (beta-VLDL) clearance in vivo.
Main Results:
- Plasma apo E variant levels varied significantly among founder mice and correlated directly with hyperlipidemia.
- High expression of the apo E variant led to grossly elevated plasma lipids and the presence of beta-VLDL.
- Transgenic mouse beta-VLDL showed impaired clearance in normal mice, indicating defective catabolism.
- While enriched in cholesteryl esters, mouse beta-VLDL were less cholesterol-rich than human counterparts.
Conclusions:
- Transgenic mice expressing high levels of the dysfunctional apo E (Arg-112, Cys-142) variant exhibit key features of human type III HLP.
- This model demonstrates dose-dependent effects of the apo E variant on lipid metabolism.
- The impaired clearance of beta-VLDL in these mice highlights a critical aspect of type III HLP pathogenesis.
- These mice represent a suitable preclinical model for investigating type III HLP and testing potential therapies.
