Lipoprotein [a] is cleared from the plasma primarily by the liver in a process mediated by apolipoprotein [a].
The cellular and molecular mechanisms responsible for lipoprotein [a] (Lp[a]) catabolism are unknown. We examined the plasma clearance of Lp[a] and LDL in mice using lipoproteins isolated from human plasma coupled to radiolabeled tyramine cellobiose. Lipoproteins were injected into wild-type, LDL receptor-deficient (Ldlr-/-), and apolipoprotein E-deficient (Apoe-/-) mice. The fractional catabolic rate of LDL was greatly slowed in Ldlr-/- mice and greatly accelerated in Apoe-/- mice compared with wild-type mice. In contrast, the plasma clearance of Lp[a] in Ldlr-/- mice was similar to that in wild-type mice and was only slightly accelerated in Apoe-/- mice. Hepatic uptake of Lp[a] in wild-type mice was 34.6% of the injected dose over a 24 h period. The kidney accounted for only a small fraction of tissue uptake (1.3%). To test whether apolipoprotein [a] (apo[a]) mediates the clearance of Lp[a] from plasma, we coinjected excess apo[a] with labeled Lp[a]. Apo[a] acted as a potent inhibitor of Lp[a] plasma clearance. Asialofetuin, a ligand of the asialoglycoprotein receptor, did not inhibit Lp[a] clearance. In summary, the liver is the major organ accounting for the clearance of Lp[a] in mice, with the LDL receptor and apolipoprotein E having no major roles. Our studies indicate that apo[a] is the primary ligand that mediates Lp[a] uptake and plasma clearance.
Cain
William J
WJ
Department of Biological Sciences, University of Delaware, Newark, DE, USA. will@udel.edu
Millar
John S
JS
Himebauch
Adam S
AS
Tietge
Uwe J F
UJ
Maugeais
Cyrille
C
Usher
David
D
Rader
Daniel J
DJ
D000818:Animals; D001054:Apolipoproteins A / Q000097:blood / Q000378:metabolism*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D001212:Asialoglycoproteins / Q000097:blood; D008078:Cholesterol, LDL / Q000378:metabolism; D060748:Fetuins; D017270:Lipoprotein(a) / Q000097:blood* / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000509:alpha-Fetoproteins
D001054:Apolipoproteins A; D001057:Apolipoproteins E; D001212:Asialoglycoproteins; D008078:Cholesterol, LDL; D060748:Fetuins; D017270:Lipoprotein(a); D011973:Receptors, LDL; D000509:alpha-Fetoproteins; C017029:asialofetuin