17 Facts About PCSK9

The PCSK9 gene contains one of 27 loci associated with increased risk of coronary artery disease.

PCSK9 is ubiquitously expressed in many tissues and cell types.

PCSK9 has medical importance because it acts in lipoprotein homeostasis.

In that same year, investigators at Rockefeller University and University of Texas Southwestern had discovered the same protein in mice, and had worked out the novel pathway that regulates LDL cholesterol in which PCSK9 is involved, and it soon became clear that the mutations identified in France led to excessive PCSK9 activity, and thus excessive removal of the LDL receptor, leaving people carrying the mutations with too much LDL cholesterol.

The secretion of PCSK9 is largely dependent on the autocleavage of the signal peptide and N-terminal prodomain, though the N-terminal prodomain retains its association with the catalytic domain.

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PCSK9 is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum.

PCSK9 is expressed mainly in the liver, the intestine, the kidney, and the central nervous system.

PCSK9 plays an important role in intestinal triglyceride-rich apoB lipoprotein production in small intestine and postprandial lipemia.

The plasma PCSK9 concentration is higher in women compared to men, and the PCSK9 concentrations decrease with age in men but increase in women, suggesting that estrogen level most likely plays a role.

In humans, PCSK9 was initially discovered as a protein expressed in the brain.

Recent evidence indicate that PCSK9 is highly expressed in arterial walls such as endothelium, smooth muscle cells, and macrophages, with a local effect that can regulate vascular homeostasis and atherosclerosis.

Accordingly, it is very clear that PCSK9 has pro-atherosclerotic effects and regulates lipoprotein synthesis.

Multi-locus genetic risk score study based on a combination of 27 loci including the PCSK9 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy.

Drugs can inhibit PCSK9, leading to lowered circulating LDL particle concentrations.

An FDA warning in March 2014 about possible cognitive adverse effects of PCSK9 inhibition caused concern, as the FDA asked companies to include neurocognitive testing into their Phase III clinical trials.

Vaccine that targets PCSK9 has been developed to treat high LDL-particle concentrations.

Mice and macaques vaccinated with bacteriophage VLPs displaying PCSK9-derived peptides developed high-titer IgG antibodies that bound to circulating PCSK9.