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<http://www.sciencedaily.com/releases/2004/04/040427055424.htm Source:      Rockefeller University Date:      2004-04-27   Print this page Email to friend 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. GENE IN GREEN: This red and green photo shows that high levels of active Pcsk9 gene prevents LDL cholesterol from binding to the surface of liver cells. LDL cholesterol was labeled with red, glow-in-the-dark dye while the Pcsk9 gene was labeled with green. Green cells with high levels of Pcsk9 inside have little or no red border, which means that LDL cholesterol molecules are not bound to their surfaces. Cells without high levels of Pcsk9 inside appear red because red LDL molecules are bound to their surfaces. (Image courtesy Rockefeller University) 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 _meta_bolism 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 _link_ed 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 _link_ed 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 injected the virus into normal mice, where it made Pcsk9 protein inside liver cells. With abnormally high levels of Pcsk9 in their livers, the mice developed high cholesterol. Four days after injection, the animals' LDL levels were five times the normal level, and their levels of total cholesterol in the bloodstream had doubled. (Total cholesterol measures LDL plus HDL plus another type of cholesterol.) Maxwell suspected that the Pcsk9 protein was raising LDL levels by acting on the liver cells' LDL receptors, which snatch up LDL molecules from the blood. To test this hypothesis, Maxwell injected the Pcsk9-carrying virus into a strain of mice that do not have LDL receptors because of a genetic defect. When Maxwell examined the special high-cholesterol mice after they had been injected with Pcsk9, she found that their cholesterol levels had not changed