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Newly discovered gene controls levels of 'bad' cholesterol in mice

Using mice as test subjects, the Rockefeller scientists determined that the gene, called Pcsk9, can decrease the number of receptors on liver cells that remove the "bad" LDL cholesterol from the blood.

"It's very exciting to think that Pcsk9 might play a large role in the pathway to regulate the uptake of bad cholesterol from blood," said Kara Maxwell, the lead researcher of the study published this week in the journal Proceedings of the National Academy of Sciences. Maxwell is an M.D.-Ph.D. student in the Laboratory of Biochemical Genetics and Metabolism headed by Jan L. Breslow, M.D., the senior author of the study.

High levels of LDL cholesterol in the blood lead to heart attacks because the waxy LDL molecules build up inside the walls of arteries, causing damage to the blood vessels and leading to clots that block the follow of blood to the heart muscle.

Maxwell's cholesterol study in mice is highly relevant to humans because mutant forms of the Pcsk9 gene have been linked to one form of autosomal dominant hypercholesterolemia, a group of genetic disorders characterized by excessive levels of cholesterol in the bloodstream.

To identify genes that regulate cholesterol levels in the blood in response to high cholesterol diets, Maxwell examined gene activity in mice that were fed normal diets and mice that were fed high-cholesterol diets. In this experiment she found a previously unknown gene, now called Pcsk9, that was expressed at a much lower level in mice that were fed high-cholesterol diets compared to mice that were fed normal diets.

Last year, a research team led by Nabil Seidah and Catherine Boileau at the Hospital Necker-Enfants Malades in France independently found that mutations in the Pcsk9 gene were linked to autosomal dominant hypercholesterolemia. But the function of Pcsk9 was not determined until now.

To find out what Pcsk9 does, Maxwell inserted the Pcsk9 gene into a virus that targets the liver and
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26-Apr-2004


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