Our studies have identified a soluble molecule in normal human plasma and serum with the characteristics of the ␣-chain of the low density lipoprotein receptorrelated protein (LRP). LRP is a large multifunctional receptor mediating the clearance of diverse ligands, including selected lipoproteins, various protease inhibitor complexes, and thrombospondin. A soluble molecule (sLRP) has been isolated from plasma using an affinity matrix coupled with methylamine-activated ␣ 2 -macroglobulin, the ligand uniquely recognized by LRP, and eluted with EDTA. This eluate contains a protein that co-migrates on SDS-polyacrylamide gel electrophoresis with authentic human placental LRP ␣-chain, is recognized by anti-LRP ␣-chain monoclonal antibodies, and binds the 39-kDa receptor-associated protein (RAP) and tissue plasminogen activator-inhibitor complexes. A similar RAP-binding molecule was detected in medium conditioned for 24 h by primary cultures of rat hepatocytes, suggesting that the liver may be the in vivo source of sLRP. In contrast, immunoprecipitation experiments failed to detect the production of sLRP by cultured HepG2 hepatoma and primary human fibroblast cells. Addition of a soluble form of LRP to cultured HepG2 cells resulted in a significant inhibition of capacity of these cells to degrade tPA, a process that has been demonstrated to be mediated by cell surface LRP. Preliminary data indicate that the concentration of sLRP is altered in the plasma of patients with liver disease. Increased levels of sLRP may antagonize the clearance of ligands by cell bound LRP perturbing diverse processes including lipid metabolism, cell migration and extracellular proteinase activity.The low density lipoprotein receptor-related protein (LRP) 1 has been previously identified as a membrane-bound endocytic receptor (1, 2). Studies have demonstrated that LRP mediates the internalization of multiple, structurally unrelated ligands, including selected lipoproteins, proteinase-inhibitor complexes, plasminogen activators, and thrombospondin (reviewed in Refs. 3 and 4). The binding of all ligands to LRP is inhibited by the receptor-associated protein (RAP), a protein that was copurified with LRP (2, 5). The range of ligands recognized by LRP suggests that it plays a role in diverse processes including lipid metabolism, cell growth, migration, and tissue invasion. LRP expression is widespread; however, it is most highly expressed in the liver, brain, and placenta. The remarkable degree of cross-species identity conserved in the LRP amino acid sequence (3) and the embryonic lethal phenotype obtained after targeted disruption of the LRP gene in the mouse (6) underscore the biological importance of this molecule.Here we report the identification of a soluble form of LRP circulating in human plasma. The characterization of this molecule, which maintains the ligand binding characteristics of cell surface LRP, introduces a new dimension to the biology of LRP. Accumulation of soluble LRP in plasma may antagonize the clearance of ligands by cell-...