An Apolipoprotein that Strongly Modulates Plasma Triglyceride Levels
APPLICATIONS OF TECHNOLOGY:
- Creation of new lipid-reducing drugs - Large scale genetic screening of individuals for cardiovascular disease susceptibility - Delivery of the ApoAV protein to reduce high triglyceride and VLDL levels in humans - Gene therapy potential for this liver-specific gene - Direct plasma administration of the protein - Examination of constructed mouse lines to study ApoAV’s function and to test therapies. - Transgenic mice have 70% reduced triglycerides - Knockout mice have 400% increased triglycerides.
- Early diagnosis and treatment of genetically induced cardiovascular disease - Identification of the extremely large number of people, ~20 - 40% of Caucasians, with ApoAV polymorphisms that cause increased levels of plasma triglycerides - The strength of the created mouse models, which will be extremely effective for studying the human gene and for testing future therapies
Summary: Scientists at Berkeley Lab have found a new apolipoprotein gene that greatly influences both human and mouse triglyceride and VLDL levels, both of which are a major risk factor for cardiovascular disease.
The human gene, which Edward Rubin and Len Pennacchio have named ApoAV, was discovered near the ApoAI/CIII/AIV cluster of apolipoprotein genes on human chromosome 11. This region is known to have a major influence on plasma lipid profiles and, consequently, atherosclerosis susceptibility. It is also well known that mutations in DNA sequences within this region can contribute to severely elevated triglyceride levels, although such sequence changes are extremely rare. Rubin and Pennacchio have collected strong data supporting a major effect of human ApoAV variants in determining population-based increases in plasma triglyceride levels. Their further studies in mice provided consistent results with the clinical findings.
Research: The human ApoAV gene was introduced into a line of mice through standard transgenic technology and engineered to over-express itself. In addition, using gene knockout technology, Rubin and Pennacchio also engineered mice that lacked ApoAV. Comparing the two groups revealed a dramatic contrast.
“Mice with increased expression of human ApoAV showed a 70-percent decrease in plasma triglyceride concentrations while mice lacking ApoAV (the ApoAV knockouts) showed a 400-percent increase,” says Pennacchio. “The results from the two studies strongly supported one another.”
Most importantly, when they extended their studies to the human population they made a profound discovery. Human ApoAV polymorphisms were found to be strongly associated with triglycerides in the general population, consistent with their findings in mouse studies. These ApoAV variants are found in 10% of human chromosomes and are associated with an approximately 30% increase in plasma triglycerides. Furthermore, Rubin and Pennacchio were able to replicate their initial result, which supports the finding that about one in five individuals in the population has increased triglycerides due to variation in the human ApoAV gene.
Clinical and Pharmaceutical Applications: Using the ApoAV gene for early detection, diagnosis, and treatment of genetically induced cardiovascular disease may have a profound clinical impact. The possibilities for application are vast. Drug therapies can be designed to raise the levels of this protein in human patients with high VLDL levels, thus reducing VLDL and triglyceride levels and reducing the risk of cardiovascular disease. The protein can be used in screening to identify gene abnormalities that lead to cardiovascular disease. Direct delivery of the ApoAV protein or a mimicking molecule in someone with high VLDL levels may reduce those levels.
Edward Rubin and Len Pennacchio
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