On the function and homeostasis of PCSK9: reciprocal interaction with LDLR and additional lipid effects

Atherosclerosis. 2015 Feb;238(2):264-70. doi: 10.1016/j.atherosclerosis.2014.12.017. Epub 2014 Dec 17.


Proprotein convertase subtilisin kexin type 9 (PCSK9) is a circulatory ligand that terminates the lifecycle of the low-density lipoprotein (LDL) receptor (LDLR) thus affecting plasma LDL-cholesterol (LDL-C) levels. Recent evidence shows that in addition to the straightforward mechanism of action, there are more complex interactions between PCSK9, LDLR and plasma lipoprotein levels, including: (a) the presence of both parallel and reciprocal regulation of surface LDLR and plasma PCSK9; (b) a correlation between PCSK9 and LDL-C levels dependent not only on the fact that PCSK9 removes hepatic LDLR, but also due to the fact that up to 40% of plasma PCSK9 is physically associated with LDL; and (c) an association between plasma PCSK9 production and the assembly and secretion of triglyceride-rich lipoproteins. The effect of PCSK9 on LDLR is being successfully utilized toward the development of anti-PCSK9 therapies to reduce plasma LDL-C levels. Current biochemical research has uncovered additional mechanisms of action and interacting partners for PCSK9, and this opens the way for a more thorough understanding of the regulation, metabolism, and effects of this interesting protein.

Keywords: Low-density lipoprotein; Low-density lipoprotein receptor; Pleiotropic effects; Proprotein convertase subtilisin kexin 9; Protein interaction.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Cholesterol, LDL / blood
  • Dyslipidemias / blood
  • Dyslipidemias / drug therapy
  • Dyslipidemias / enzymology*
  • Enzyme Inhibitors / therapeutic use
  • Homeostasis
  • Humans
  • Hypolipidemic Agents / therapeutic use
  • Lipid Metabolism* / drug effects
  • Molecular Targeted Therapy
  • Proprotein Convertase 9
  • Proprotein Convertases / antagonists & inhibitors
  • Proprotein Convertases / blood
  • Proprotein Convertases / metabolism*
  • Protein Binding
  • Receptors, LDL / blood
  • Receptors, LDL / metabolism*
  • Serine Endopeptidases / blood
  • Serine Endopeptidases / metabolism*
  • Triglycerides / blood


  • Cholesterol, LDL
  • Enzyme Inhibitors
  • Hypolipidemic Agents
  • Receptors, LDL
  • Triglycerides
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases