A team of researchers from the University of Pennsylvania Medical Center and Rhone-Poulenc Rorer has identified a new human gene that may figure prominently in the regulation of cholesterol levels in the body. When the gene was experimentally overexpressed in mice, levels of the form of cholesterol called high-density lipoprotein, or HDL, dropped to nearly undetectable levels, a condition that would be associated with high cardiovascular disease risk in humans. A report on the new findings appears in the April issue of Nature Genetics.
"HDL is a very powerful protector against heart disease and stroke, and we think this new gene could be a major player in determining HDL levels," says Daniel J. Rader, MD, an assistant professor of medicine and senior author on the report. "Too much activity on the part of this gene, for whatever reason, might lead to lowered HDL levels and higher cardiovascular disease risk."
While high overall levels of cholesterol in the blood have long been linked to elevated cardiovascular disease risk, two distinct forms of cholesterol are involved, each performing different duties in the body. Low-density lipoprotein (LDL) - sometimes called the bad cholesterol - is produced by the liver and ferries fats to the muscles, the heart, and other tissues. Unchecked, this process can lead to the formation of dangerous deposits in the arteries that can disrupt or block blood flow. HDL - referred to as the good cholesterol -- is also produced by the liver and is responsible for returning fats from tissues in the body to the liver for reprocessing or elimination. Dramatically lowered HDL levels could, therefore, lead to a health crisis in time.
Scientists have known that at least 50 percent of the variation in HDL cholesterol levels in the body depends on genetic factors. The specific genes involved have been unknown, however, so the current findings represent a potentially important advance toward understanding processes that contribute significantly to cardiovascular disease risk.
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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