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Heparan sulfate proteoglycans present PCSK9 to the LDL receptor
Aarhus Univ, Dept Biomed, Ole Worms Alle 3, DK-8000 Aarhus, Denmark..
Aarhus Univ, Dept Biomed, Ole Worms Alle 3, DK-8000 Aarhus, Denmark..
Aarhus Univ, Dept Mol Biol & Genet, Gustav Wieds Vej 10, DK-8000 Aarhus, Denmark..
Aarhus Univ, Dept Biomed, Ole Worms Alle 3, DK-8000 Aarhus, Denmark..
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2017 (engelsk)Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikkel-id 503Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
2017. Vol. 8, artikkel-id 503
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-335195DOI: 10.1038/s41467-017-00568-7ISI: 000410237600005PubMedID: 28894089OAI: oai:DiVA.org:uu-335195DiVA, id: diva2:1163659
Tilgjengelig fra: 2017-12-07 Laget: 2017-12-07 Sist oppdatert: 2017-12-07bibliografisk kontrollert

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