Heparan sulfate proteoglycans present PCSK9 to the LDL receptor

Camilla Gustafsen (), Ditte Olsen, Joachim Vilstrup, Signe Lund, Anika Reinhardt, Niels Wellner, Torben Larsen, Christian B. F. Andersen, Kathrin Weyer, Jin-ping Li, Peter H. Seeberger, Søren Thirup, Peder Madsen and Simon Glerup ()
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Camilla Gustafsen: Aarhus University
Ditte Olsen: Aarhus University
Joachim Vilstrup: Aarhus University
Signe Lund: Aarhus University
Anika Reinhardt: Scienion AG
Niels Wellner: Aarhus University
Torben Larsen: Aarhus University
Christian B. F. Andersen: Aarhus University
Kathrin Weyer: Aarhus University
Jin-ping Li: University of Uppsala
Peter H. Seeberger: Max Planck Institute for Colloids and Interfaces
Søren Thirup: Aarhus University
Peder Madsen: Aarhus University
Simon Glerup: Aarhus University

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Coronary artery disease is the main cause of death worldwide and accelerated by increased plasma levels of cholesterol-rich low-density lipoprotein particles (LDL). Circulating PCSK9 contributes to coronary artery disease by inducing lysosomal degradation of the LDL receptor (LDLR) in the liver and thereby reducing LDL clearance. Here, we show that liver heparan sulfate proteoglycans are PCSK9 receptors and essential for PCSK9-induced LDLR degradation. The heparan sulfate-binding site is located in the PCSK9 prodomain and formed by surface-exposed basic residues interacting with trisulfated heparan sulfate disaccharide repeats. Accordingly, heparan sulfate mimetics and monoclonal antibodies directed against the heparan sulfate-binding site are potent PCSK9 inhibitors. We propose that heparan sulfate proteoglycans lining the hepatocyte surface capture PCSK9 and facilitates subsequent PCSK9:LDLR complex formation. Our findings provide new insights into LDL biology and show that targeting PCSK9 using heparan sulfate mimetics is a potential therapeutic strategy in coronary artery disease.

Date: 2017
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DOI: 10.1038/s41467-017-00568-7

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