Heparan sulfate proteoglycans present PCSK9 to the LDL receptor

TY - JOUR

T1 - Heparan sulfate proteoglycans present PCSK9 to the LDL receptor

AU - Gustafsen, Camilla

AU - Olsen, Ditte

AU - Vilstrup, Joachim

AU - Lund, Signe

AU - Reinhardt, Anika

AU - Wellner, Niels

AU - Larsen, Torben

AU - Andersen, Christian B F

AU - Weyer, Kathrin

AU - Li, Jin-Ping

AU - Seeberger, Peter H

AU - Thirup, Søren

AU - Madsen, Peder

AU - Glerup, Simon

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

KW - Journal Article

UR - http://www.scopus.com/inward/record.url?scp=85029303059&partnerID=8YFLogxK

U2 - 10.1038/s41467-017-00568-7

DO - 10.1038/s41467-017-00568-7

M3 - Journal article

C2 - 28894089

SN - 2041-1723

VL - 8

SP - 503

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 503

ER -