Increasing Bad Cholesterol Levels

Low-density lipoproteins (LDLs, also known as "bad cholesterol") are removed from the bloodstream by binding to LDL receptors (LDLRs) present on the surface of cells. After binding, cells internalize both the receptor and cholesterol, the cholesterol is processed by the cell and LDLR is recycled back to the surface, where it can bind new cholesterol molecules. The amount of surface LDLR is decreased by the PCSK9 protein, resulting in high blood cholesterol, but how PCSK9 does this was not known. Xiayang Qiu and colleagues have now found that PCSK9 binds very tightly to LDLR. This tight binding may lower LDLR levels on the cell surface by sequestering LDLRs inside cells, preventing their recycling back to the cell surface. A mutation in PCSK9 associated with high cholesterol shows even tighter binding to LDLR, supporting this model. These findings should improve our understanding of cholesterol regulation, and may help in the development of drugs to treat cardiovascular disease.

Author contact:

Xiayang Qiu (Pfizer, Groton, CT, USA)
E-mail: xiayang.qiu@pfizer.com

Abstract available online.

(C) Nature Structural & Molecular Biology press release.

Message posted by: Trevor M. D'Souza