Figure 1.

PCSK9 role in the liver (A) and mechanism of action of anti‐PCSK9 monoclonal antibodies (mAbs) (B). (A) The low‐density lipoprotein receptor (LDLR) expressed on the cell surface of hepatocytes binds to low‐density lipoprotein (LDL) particles and undergoes endocytosis. When proprotein convertin subtilisin/kexin type 9 (PCSK9) is secreted from hepatocytes and binds to the LDLR on the cell surface, LDLR recycling to the cell surface is blocked and the LDLR instead traffics to the lysosome where it is degraded. In the acidic environment of the endosome, LDL dissociates from the LDLR and both are degraded in the lysosome to their component lipids and amino acids. The ability of PCSK9 to promote LDLR degradation results in decreased LDLR levels at the cell surface and consequently an increase in serum LDL levels. (B) The interaction between PCSK9 and LDLR can be prevented by anti‐PCSK9 mAbs that specifically bind to PCSK9. In the absence of PCSK9 bound to LDLR, the complex formed by LDLR and LDL is internalised in an endosome that allows LDLR recycling to the cell surface instead of its lysosomal degradation. LDLR recycling results in increased LDLR levels at the cell surface, allowing further rounds of LDL uptake and degradation, and consequent reduction in serum LDL levels