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Smooth regulation of lipid metabolism

As published in the November 15th issue of Genes & Development, a collaboration between a medical school and a biotech company gives hope in the fight against cardiovascular disease. The teams of Dr. David Mangelsdorf at the Howard Hughes Medical Institute at the University of Texas Southwestern Medical Center in Dallas and Dr. Bei Shan at Tularik Inc. in San Franscico report in two joint publications on their progress in understanding the molecular mechanisms of cholesterol metabolism.

Increased serum lipid levels are linked to disorders like diabetes and cardiovascular disease. Cholesterol is a major component of serum lipids. Normally, cholesterol is removed from the blood stream and processed for storage, degraded and secreted, or remodeled into other lipids. One important receptor for cholesterol derivatives is a gene regulator known as LXRa. The first of these two articles identifies SREBP-1c, a novel gene target of LXRa. The SREBP-1c protein is also a gene regulator; it in turn controls the expression of lipogenic enzymes. It was previously known that SREBP-1c played a role in the regulation of serum lipid levels. However, the exciting new discovery that this gene also forms the second step of a two-part lipid level control mechanism might help to design new strategies to treat these diseases.

The approach to develop potential disease therapies is detailed in the second of these two articles. Shan and colleagues screened more than 300,000 chemicals for novel compounds which bind to LXRa. Two related synthetic compounds were identified, and then used to further study the LXRa pathway. Not surprisingly, SREBP-1c turned out once again to be a major player downstream of LXRa. While the molecules identified are most useful as research tools to further unravel the pathways involved, their discovery might lead to the identification of specific LXRa antagonists. These drugs could then be used as therapeutics to interfere with the now more clearly delineated pathway linking high cholesterol status to increased lipid levels in the blood.

Cold Spring Harbor Laboratory. November 2000.

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