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Insight into natural cholesterol control suggests novel cholesterol-lowering therapy

New work reported in the March issue of Cell Metabolism has provided insight into a key mechanism by which cells limit cholesterol synthesis. The finding suggests a novel approach to the development of cholesterol-lowering drugs that may boost the effect of statins, one of the most prescribed cholesterol inhibitors, according to researchers at the University of Texas Southwestern Medical Center.

Cells obtain cholesterol, an important component of cell membranes, by building it internally or by taking it up from the bloodstream. The cholesterol-building process involves more than 25 enzymes, including one called HMG CoA reductase, and many layers of regulatory control, said Russell DeBose-Boyd, senior author of the study.

Scientists have long known that cells respond to a high cholesterol diet by shutting down its internal synthesis, he explained. However, the molecular mechanisms by which cholesterol and other related compounds exert that self-control have only more recently begun to emerge.

The researchers now demonstrate that lanosterol--an intermediate compound in the synthetic pathway--mediates feedback control over the rate of cholesterol production by stimulating the degradation of cholesterol-building reductase. The availability of reductase, which functions early in the synthetic process, largely determines the rate of cellular cholesterol production, Debose-Boyd said.

When added to intact cells and cellular components in test tubes, lanosterol led other proteins to mark reductase for destruction by attaching a protein called ubiquitin in a process called ubiquitination. Ubiquitination is a common mechanism for stimulating protein degradation. Cholesterol itself had no such effect on reductase, even at much greater concentrations, they found.

"The current results demonstrate a direct role for lanosterol as a selective, physiologic regulator of reductase ubiquitination and degradation," said DeBose-Boyd. That effect wou
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Contact: Heidi Hardman
hhardman@cell.com
1-617-397-2979
Cell Press
15-Mar-2005


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