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 would, in turn, control the rate of cholesterol production.

"In addition to the biological significance, the findings have important clinical implications for cholesterol control," he said.

Cholesterol-lowering statins--taken by an estimated 10 million people each day to protect against coronary artery disease and reduce the incidence of heart attacks--limit cholesterol synthesis by inhibiting reductase function, he said. As a result, cells take up more cholesterol from the bloodstream, lowering its concentration there.

However, inhibition of reductase function by statins also limits the availability of regulatory intermediates that govern reductase activity, contributing to a major increase in active reductase that becomes progressively harder to control, according to the researchers. The new findings suggest that drugs that mimic lanosterol--given along with statins--may improve the drugs' long-term ability to lower cholesterol by stimulating reductase degradation.

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The other members of the research team include Bao-Liang Song and Russell A. DeBose-Boyd from University of Texas Southwestern Medical Center; and Norman B. Javitt from New York University School of Medicine. The work was supported by research grants from the National Institutes of Health (HL20948), Perot Family Foundation, and W.M. Keck Foundation. R.A.D.-B. is the recipient of a National Institutes of Health Mentored Minority Faculty Development Award (HL70441) and an Established Investigator Award from the American Heart Association.

Bao-Liang Song, Norman B. Javitt, and Russell A. DeBose-Boyd: "Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterol"

Publishing in Cell Metabolism, Volume 1, Number 3, March 2005, pages 179-189. www.cellmetabolism.org

Source : Cell Press