Finally, the LDL receptor joins in

Comment on Bovenschen et al, page 906

The LDL receptor is a member of a family of gene products with partially overlapping function. In this issue of Blood, Bovenschen and colleagues describe how members of the LDL receptor gene family cooperate in the regulation of factor VIII.

The LDL receptor (LDLR) binds apolipoproteins E and B-100¹  and is part of a gene family that includes truly multifunctional proteins. In this issue, Bovenschen and colleagues demonstrate a role for the LDLR in factor VIII catabolism.

The LDLR gene family includes over 10 proteins that regulate many aspects of cell physiology.^2,3  LDLR-related protein-1 (LRP-1) binds over 40 known ligands. Multiple receptors in the LDLR family function in cell signaling. The very low-density lipoprotein (VLDL) receptor, apolipoprotein E receptor-2, and LRP 5/6 have been implicated in specific aspects of development. LRP-1 deficiency is lethal in embryonic mice, indicating broad-reaching activity in development.

The ability of LRP-1 to regulate the composition of the plasma membrane is an exciting, emerging topic. One membrane protein regulated by LRP-1 is tissue factor, suggesting a role for LRP-1 in hemostasis.⁴  LRP-1 also regulates hemostasis by functioning as an endocytic receptor for plasminogen activators and Serpin-protease complexes.

Understanding the catabolism of factor VIII may provide new insight into hemophilia and von Willebrand disease. Thus, the recent identification of LRP-1 as the major receptor for factor VIII is an important step forward. The authors of this paper previously demonstrated that factor VIII is significantly elevated in the plasma when the LRP-1 gene is conditionally inactivated in liver.⁵  It also has been shown that plasma factor VIII increases when the LRP-1 antagonist, receptor-associated protein (RAP), is delivered by intravenous injection or adenovirus expression.^5,6  However, the activity of RAP may not be exclusively due to inhibition of LRP-1.

RAP antagonizes the endocytic activity of multiple receptors in the LDLR family, including the LDLR itself, and in their new study, Bovenschen and colleagues demonstrate that the LDLR is a receptor for factor VIII. Their results demonstrate that the LDLR functions in a “back-up” mode, supporting LRP-1 in factor VIII regulation. LDLR deficiency does not increase plasma factor VIII in mice unless hepatic LRP-1 is neutralized, in which case the effect of LDLR deficiency is substantial. Adenovirus-mediated LDLR expression in LDLR/LRP-1–deficient mice significantly increases the kinetics of factor VIII clearance.

Well-executed in vitro binding experiments mirror the function of the LDLR and LRP-1 as factor VIII receptors in vivo. In direct-binding and binding-competition studies, soluble LDLR binds factor VIII but with decreased affinity compared with LRP-1 ligand–binding cluster 2. The difference in affinity was less than an order of magnitude. The VLDL receptor also binds factor VIII; however, the function of this receptor in factor VIII clearance may be compromised by its slow rate of endocytosis.

Despite the outstanding advances in the present paper, questions remain. The dynamic interaction of factor VIII with LDLR family members and von Willebrand factor (VWF) merits further attention. vWF does not bind to the LDLR or LRP-1, but is elevated when these receptors are neutralized. Does this reflect a novel in vivo cell-signaling/transcription regulation pathway? ▪