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Liver cells pull LDL cholesterol out of the blood using receptors on their surface. PCSK9 destroys those receptors, so more cholesterol stays in circulation. People born with a broken PCSK9 gene have low cholesterol and appear entirely healthy — which is exactly why it is such an attractive target: nature has already run the experiment.
PCSK9, at 1p32.3, encodes a protease that binds the LDL receptor and directs it to lysosomal degradation, reducing hepatic LDL clearance. Loss-of-function variants are associated with lifelong low LDL cholesterol and reduced cardiovascular events without evident harm; gain-of-function variants cause familial hypercholesterolemia. It is validated as a drug target by approved monoclonal antibodies and siRNA medicines, and is the target of in vivo base-editing programmes intended to make the effect permanent.
Sources
- New England Journal of Medicine (Cohen et al.) · 2006
Sequence variations in PCSK9, low LDL, and protection against coronary heart disease ↗