A novel efflux-recapture process underlies the mechanism of high-density lipoprotein cholesteryl ester-selective uptake mediated by the low-density lipoprotein receptor-related protein.
OBJECTIVE
To determine the mechanism of low-density lipoprotein (LDL) receptor-related protein (LRP)-mediated selective uptake of high-density lipoprotein (HDL)-derived cholesteryl esters (CE).


RESULTS
Apolipoprotein E (apoE) and heparin sulfate proteoglycans are required for LRP-mediated selective uptake in adipocytes. Furthermore, 2-deoxyglucose and NaN(3) abolish this process, indicating that cellular energy is required. LRP-mediated selective uptake is also abolished by monensin or when clathrin-mediated internalization is inhibited (using hypotonic, K(+)-free medium or hyperosmolar sucrose), clearly implicating receptor endocytosis. The receptor-associated protein (RAP), an inhibitor of ligand binding to LRP, reduced the transport of CE into an intracellular compartment but not into the plasma membrane. Remarkably, the CE that is ultimately transported by LRP first enters the plasma membrane then undergoes apoE-mediated CE efflux before being recaptured and internalized by LRP.


CONCLUSIONS
According to this "efflux-recapture" model, LRP contributes to selective uptake because it recovers CE that would normally be lost by efflux mediated by apoE. In adipocytes, the LDL receptor-related protein contributes to selective uptake when it recaptures and internalizes HDL-derived cholesteryl esters that are otherwise lost by apoE-mediated efflux. This novel "efflux-recapture" process explains some conflicting observations of selective uptake and underscores the bi-directional nature of efflux.
Vassiliou
Gerard
G
Lipoprotein and Atherosclerosis Group, Lab H453, University of Ottawa Heart Institute, Ottawa ON K1Y 4W7, Canada. gvass@ottawaheart.ca
McPherson
Ruth
R
D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D001692:Biological Transport; D045744:Cell Line, Tumor / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured / Q000378:metabolism; D002704:Chlorates / Q000494:pharmacology; D002788:Cholesterol Esters / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism*; D019765:Chondroitin ABC Lyase / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology; D004822:Epididymis; D005347:Fibroblasts / Q000378:metabolism; D006493:Heparin / Q000031:analogs & derivatives* / Q000378:metabolism; D019763:Heparin Lyase / Q000494:pharmacology; D006801:Humans; D006923:Hymecromone / Q000031:analogs & derivatives* / Q000494:pharmacology; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D008080:Liposarcoma / Q000473:pathology; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D011509:Proteoglycans / Q000378:metabolism; D019810:Sodium Azide / Q000494:pharmacology
D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D002704:Chlorates; D002788:Cholesterol Esters; D008078:Cholesterol, LDL; D026502:LDL-Receptor Related Proteins; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D011509:Proteoglycans; C036090:heparin proteoglycan; D006923:Hymecromone; C014111:methylumbelliferyl-beta-D-xyloside; D006493:Heparin; D019810:Sodium Azide; D003847:Deoxyglucose; D019765:Chondroitin ABC Lyase; D019763:Heparin Lyase