Why PCSK9 Raises Cholesterol Levels

Main Category: Cholesterol
Article Date: 06 Nov 2006 - 4:00 PDT

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Some individuals have increased activity of a protein known as PCSK9 because they have a mutation in one of their genes encoding this protein. This genetic defect causes individuals to have high levels of cholesterol in their blood. Although it is known that this is because PCSK9 decreases the number of receptors that remove cholesterol from the blood (LDLRs) expressed by cells in the liver, the mechanisms by which this occurs have not been previously determined. Now, in a study appearing in the November issue of the Journal of Clinical Investigation, researchers at the University of Texas Southwestern have shown that PCSK9 functions to decrease LDLR levels from outside the cell.

Jay Horton and colleagues found that PCSK9 bound to LDRLs on the surface of liver cells and caused the LDLRs to be internalized. Importantly, PCSK9 in the blood system of one mouse was able to decrease the levels of LDLR found at the surface of liver cells of another mouse, causing cholesterol levels to rise. Because this study shows that PCSK9 in the blood regulates the level of LDLR expressed by liver cells, the authors suggest that blocking PCSK9 function in the blood might provide a new approach for developing drugs to treat individuals with high levels of cholesterol.

TITLE: Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice

AUTHOR CONTACT:

Jay D. Horton
University of Texas Southwestern Medical Center, Dallas, Texas, USA.

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Contact: Karen Honey
Journal of Clinical Investigation

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