Drug Targets to Increase HDL-Cholesterol Identified

Researchers working with a mouse model have identified a molecular mechanism that appears to control the production of high-density lipoprotein cholesterol (HDL-C) in liver cells.

Investigators at the University of Pennsylvania School of Medicine (Philadelphia, USA) studied a line of mice that had been genetically engineered to overexpress the liver enzyme PCSK5A. This enzyme is a member of the proprotein convertase (PC) family that has been shown to stimulate HDL-C production by inhibiting the activity of endothelial lipase (EL), the enzyme that normally degrades HDL-C. Low levels of HDL-C are a positive risk factor for atherosclerosis indicating increased likelihood of heart attack and stroke.

Results of the current study published in the August 8, 2007, issue of Cell Metabolism revealed that mice engineered to express high levels of PCSK5A had 50% higher HDL-C than control mice. Although this study was performed in mice, humans have the same proprotein convertases and endothelial lipase, and these enzymes are conserved in all vertebrates.

"This is encouraging because it suggests that either the PC or EL enzyme might be targets for drug therapy to raise good cholesterol, an unmet medical need in patients with low HDL-C,” said senior author Dr. Daniel J. Rader, professor of medicine at the University of Pennsylvania School of Medicine. "We hope to identify polymorphisms in the genes for PCs, EL, and its inhibitor that are associated with HDL-C levels, thus supporting that this pathway is relevant in humans.”


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