title: LDL receptor cooperates with LDL receptor-related protein in regulating plasma levels of coagulation factor VIII in vivo.
abstract: Low-density lipoprotein (LDL) receptor (LDLR) and LDLR-related protein (LRP) are members of the LDLR 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 LDLR family is inhibited by receptor-associated protein (RAP). We have previously reported that, apart from LRP, 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 physiologic relevance of the FVIII-LDLR interaction was addressed using mouse models of LDLR 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 or to 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.
authors.affiliation: Department of Plasma Proteins, Sanquin Research at CLB, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: Bovenschen
authors.forename: Koen
authors.initials: K
authors.lastname: Mertens
authors.forename: Lihui
authors.initials: L
authors.lastname: Hu
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Bart J M
authors.initials: BJ
authors.lastname: van Vlijmen
mesh_terms: D000818:Animals; D001665:Binding Sites; D005169:Factor VIII / Q000032:analysis / Q000378:metabolism*; D006487:Hemostasis; D006801:Humans; D026563:LDL-Receptor Related Protein-Associated Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*; D014162:Transfection
chemical_list: D026563:LDL-Receptor Related Protein-Associated Protein; D008024:Ligands; D011973:Receptors, LDL; D005169:Factor VIII