The atherogenic lipoprotein Lp(a) is internalized and degraded in a process mediated by the VLDL receptor.
Lp(a) is a major inherited risk factor associated with premature heart disease and stroke. The mechanism of Lp(a) atherogenicity has not been elucidated, but likely involves both its ability to influence plasminogen activation as well as its atherogenic potential as a lipoprotein particle after receptor-mediated uptake. We demonstrate that fibroblasts expressing the human VLDL receptor can mediate endocytosis of Lp(a), leading to its degradation within lysosomes. In contrast, fibroblasts deficient in this receptor are not effective in catabolizing Lp(a). Lp(a) degradation was prevented by antibodies against the VLDL receptor, and by RAP, an antagonist of ligand binding to the VLDL receptor. Catabolism of Lp(a) was inhibited by apolipoprotein(a), but not by LDL or by monoclonal antibodies against apoB100 that block LDL binding to the LDL receptor, indicating that apolipoprotein(a) mediates Lp(a) binding to this receptor. Removal of Lp(a) antigen from the mouse circulation was delayed in mice deficient in the VLDL receptor when compared with control mice, indicating that the VLDL receptor may play an important role in Lp(a) catabolism in vivo. We also demonstrate the expression of the VLDL receptor in macrophages present in human atherosclerotic lesions. The ability of the VLDL receptor to mediate endocytosis of Lp(a) could lead to cellular accumulation of lipid within macrophages, and may represent a molecular basis for the atherogenic effects of Lp(a).
Argraves
K M
KM
Department of Biochemistry, American Red Cross, Rockville, Maryland 20855, USA.
Kozarsky
K F
KF
Fallon
J T
JT
Harpel
P C
PC
Strickland
D K
DK
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D001161:Arteriosclerosis / Q000378:metabolism; D002474:Cell-Free System; D002478:Cells, Cultured; D004705:Endocytosis; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D007158:Immunologic Techniques; D017270:Lipoprotein(a) / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism*
D001055:Apolipoproteins B; D017270:Lipoprotein(a); D011973:Receptors, LDL; C036053:VLDL receptor