PCSK9 synthesis, secretion, and inhibition by nucleic acid-targeted therapies. PCSK9 is synthesized in the liver. After secretion, it binds to LDL-R, thus leading to LDL-R internalization and degradation (‘coupled degardation’), and preventing it from recycling. Therefore, inhibiting PCSK9 results in LDL-C reduction. LDL-R, low-density lipoprotein receptor; PCSK9, proprotein convertase subtilisin/kexin type 9.