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Blood, 1 August 2005, Vol. 106, No. 3, pp. 906-912.
Prepublished online as a Blood First Edition Paper on April 19, 2005; DOI 10.1182/blood-2004-11-4230.
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Submitted November 5, 2004
Accepted March 11, 2005
LDL receptor cooperates with LDL receptor-related protein in regulating plasma levels of coagulation factor VIII in vivo
Niels Bovenschen, Koen Mertens*, Lihui Hu, Louis M Havekes, and Bart J van Vlijmen
Department of Plasma Proteins, Sanquin Research at CLB, Amsterdam, The Netherlands; TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands
Department of Plasma Proteins, Sanquin Research at CLB, Amsterdam, The Netherlands; Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands; Department of Internal Medicine, Leiden University Medical Center (LUMC), Leiden, The Netherlands
TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands; Department of Internal Medicine, Leiden University Medical Center (LUMC), Leiden, The Netherlands; Department of Cardiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
Department of Cardiology, Leiden University Medical Center (LUMC), Leiden, The Netherlands; Department of Hematology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
* Corresponding author; email: k.mertens{at}sanquin.nl.
Low-density lipoprotein receptor (LDLR) and LDLR-related protein (LRP) are members of the LDL receptor family of endocytic receptors. LRP recognizes a wide spectrum of structurally and functionally unrelated ligands, including coagulation factor VIII (FVIII). In contrast, the ligand specificity of LDLR is restricted to apolipoproteins E and B-100. Ligand binding to the LDL receptor family is inhibited by receptor-associated protein (RAP). We have previously reported that, apart from LRP, also other RAP-sensitive mechanisms contribute to the regulation of FVIII in vivo. In the present study, we showed that the extracellular ligand-binding domain of LDLR interacts with FVIII in vitro, and that binding was inhibited by RAP. The physiological relevance of the FVIII-LDLR interaction was addressed using mouse models of LDLR and/or hepatic LRP deficiency. In the absence of hepatic LRP, LDLR played a dominant role in the regulation and clearance of FVIII in vivo. Furthermore, FVIII clearance was accelerated after adenovirus-mediated gene-transfer of LDLR. The role of LDLR in FVIII catabolism was not secondary to increased plasma lipoproteins and/or changes in lipoprotein profiles. We propose that LDLR acts in concert with LRP in regulating plasma levels of FVIII in vivo. This represents a previously unrecognized link between LDLR and hemostasis.
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