The discovery also suggests new directions for the development of pharmacological therapies for people with too-high overall cholesterol levels. "Administration of a drug able to inhibit the protein produced by this gene could be a very useful approach to raising HDL levels and preventing heart disease," according to Rader.

The protein produced by the new gene becomes the third member of a group of enzymes called triacylglyerol lipases, known to influence HDL metabolism. It is produced by endothelial cells, a subset of cells that includes those that line vessels and arteries, and is called endothelial lipase (EL).

Researchers at Rhone-Poulenc Rorer, led by Michael Jaye, PhD, a senior scientist at the company and lead author on the study, originally purified the EL protein and cloned the new gene. The Penn scientists, led by Rader, further characterized the gene and the EL protein, performing a series of experiments in mice that demonstrated the protein's likely role in HDL regulation.

For the mouse studies, Rader's group used gene transfer techniques. They stripped an adenovirus of its disease-causing genes - adenoviruses are usually associated with colds and upper respiratory infections - reloading it with the DNA needed to produce the new EL protein. They then injected the recombinant adenovirus into several strains of mice. In each case, expression of the new gene resulted in significant reductions of HDL levels in the blood.

The Penn coauthors on the study are Dawn Marchadier and Cyrille Maugcais. Additional authors at Rhone-Poulenc Rorer are Kevin J. Lynch, John Krawiec, Kim Doan, Victoria South, Dilip Amin, and Mark Perrone.

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Contact: Franklin Hoke
hokef@mail.med.upenn.edu
215-349-5659
University of Pennsylvania School of Medicine
30-Mar-1999