PCSK9

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans. PCSK9 binds to the receptor for low-density lipoprotein (LDL) cholesterol.

In the liver, the LDL receptor removes LDL cholesterol from the blood. When PCSK9 binds to the LDL receptor, the receptor is broken down and can no longer remove LDL cholesterol from the blood. If PCSK9 is blocked, more LDL receptors will be present on the surface of the liver and will remove more LDL cholesterol from the blood. Therefore, blocking PCSK9 can lower blood cholesterol levels. Similar genes (orthologs) are found across many species. PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme.

PCSK9 has medical significance because it acts in cholesterol homeostasis. Drugs can block PCSK9, thus lowering low-density lipoprotein cholesterol (LDL-C). The first two PCSK9 inhibitors, alirocumab and evolocumab, were approved by the U.S. Food and Drug Administration in 2015 for lowering cholesterol where statins and other drugs were insufficient. The manufacturers did not submit data to show that the drugs actually improved outcomes of cardiovascular disease, but they assumed that lowering cholesterol would improve cardiovascular disease.