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How bad cholesterol gets worse
Last spring, Kara Maxwell, a biomedical fellow in Jan Breslow’s Laboratory of Biochemical Genetics and Metabolism, showed that she could increase levels of LDL cholesterol (the “bad” kind) in mice by increasing the expression of a gene called PCSK9. Now, results from a new paper published in Proceedings of the National Academy of Sciences show how that happens.
Maxwell and Breslow experimented on human liver cancer cells, which they engineered to overexpress PCSK9. The extra PCSK9 caused the cells to lose their LDL receptors, which normally serve to soak up LDL cholesterol from the bloodstream. Though normal numbers of LDL receptors were manufactured, the receptor was being destroyed as it made its way to the surface of the cell.
The team’s findings complement a recent human population study in which investigators at the University of Texas Southwestern Medical Center found that about 2 percent of African-Americans with low LDL levels have mutations in the PCSK9 gene that disable the protein. Thus a picture has emerged in which too much PCSK9 decreases LDL receptors and raises LDL cholesterol levels, and too little PCSK9 does the opposite. The two papers were cited in Science magazine as the Editor’s Choice in Biomedicine for the February 11th 2005 issue.
Previous studies of LDL receptor regulation focused on how the receptor’s gene was turned on and off. “It is now clear that other genes are capable of regulating LDL receptors by different mechanisms, and LDL cholesterol lowering strategies of the future may target these genes,” says Breslow. “For example, an inhibitor of PCSK9 might act to increase liver LDL receptors and lower blood LDL cholesterol levels.”
“At this point, we don’t know the exact mechanism by which PCSK9 degrades the LDL receptor,” says Maxwell. “We are working on understanding whether PCSK9 directly destroys the receptor, or if it destroys another protein essential for the LDL receptor’s integrity. We are also developing tools to prevent PCSK9 from destroying the LDL receptor as a way to decrease blood LDL cholesterol levels.”

March 18, 2005



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