Fig. 1.

Mechanism of action for LDL lowering with statins and proprotein convertase subtilisin Kexin type 9 (PCSK9) inhibitors. The lower left of the image shows that statins inhibit HMG-CoA reductase (HMGR), which is the rate limiting step in cholesterol biosynthesis. The top section shows binding of circulating PCSK9 by human monoclonal antibody inhibitors of PCSK9. After maturation, the LDLR anchors at the cell surface and binds LDL particles via apolipoprotein B. The ligand-receptor interaction initiates receptor-mediated endocytosis. The increased pH in the lysosome degrades LDL and releases the LDLR allowing the receptor to recycle dozens of times when PCSK9 is absent. However, when PCSK9 is present, the receptor is retained in the lysosome with LDL and cannot recycle (middle right of image). Decreased intracellular cholesterol level activates SREBP-2 in the endoplasmic reticulum (lower left of image), which initiates synthesis of LDLRs allowing for binding of circulating LDL, and PCSK9 synthesis. 1. Top of form. 2. Bottom of form.

This figure was provided by Regeneron Pharmaceuticals.