Cell-associated heparin-like molecules modulate the ability of LDL to regulate PCSK9 uptake

J Lipid Res. 2019 Jan;60(1):71-84. doi: 10.1194/jlr.M087189. Epub 2018 Nov 21.


Proprotein convertase subtilisin/kexin type 9 (PCSK9) targets the LDL receptor (LDLR) for degradation, increasing plasma LDL and, consequently, cardiovascular risk. Uptake of secreted PCSK9 is required for its effect on the LDLR, and LDL itself inhibits this uptake, though how it does so remains unclear. In this study, we investigated the relationship between LDL, the PCSK9:LDLR interaction, and PCSK9 uptake. We show that LDL inhibits binding of PCSK9 to the LDLR in vitro more impressively than it inhibits PCSK9 uptake in cells. Furthermore, cell-surface heparin-like molecules (HLMs) can partly explain this difference, consistent with heparan sulfate proteoglycans (HSPGs) acting as coreceptors for PCSK9. We also show that HLMs can interact with either PCSK9 or LDL to modulate the inhibitory activity of LDL on PCSK9 uptake, with such inhibition rescued by competition with the entire PCSK9 prodomain, but not its truncated variants. Additionally, we show that the gain-of-function PCSK9 variant, S127R, located in the prodomain near the HSPG binding site, exhibits increased affinity for HLMs, potentially explaining its phenotype. Overall, our findings suggest a model where LDL acts as a negative regulator of PCSK9 function by decreasing its uptake via direct interactions with either the LDLR or HLMs.

Keywords: atherosclerosis; cholesterol; coreceptor; dyslipidemias; familial hypercholesterolemia; lipoprotein metabolism; low density lipoprotein; low density lipoprotein receptor; mechanism; proprotein convertase subtilisin/kexin type 9; receptors/lipoprotein; single nucleotide polymorphism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Expression Regulation / drug effects
  • HEK293 Cells
  • Hep G2 Cells
  • Heparin / metabolism*
  • Heparin Lyase / metabolism
  • Humans
  • Lipoproteins, LDL / metabolism*
  • Lipoproteins, LDL / pharmacology
  • Proprotein Convertase 9 / metabolism*
  • Protein Transport / drug effects
  • Receptors, LDL / metabolism


  • Lipoproteins, LDL
  • Receptors, LDL
  • Heparin
  • Proprotein Convertase 9
  • Heparin Lyase