Submitted on June 14, 2005
Revised on August 23, 2005
Accepted on August 23, 2005
Lipoprotein(a) is cleared from the plasma primarily by the liver in a process mediated by apolipoprotein(a)
William J. Cain, John S. Millar, Adam S. Himebauch, Uwe J. F. Tietge, Cyrille Maugeais, David Usher, and Daniel J. Rader
Department of Biological Sciences, University of Delaware, Newark, DE 19716
Corresponding Author: will{at}udel.edu
The cellular and molecular mechanisms responsible for Lp(a) catabolism are unknown. We examined the plasma clearance of Lp(a) and LDL in mice using lipoproteins isolated from human plasma and coupled to radiolabeled tyramine cellobiose (TC). 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 when compared to wild type . In contrast, the plasma clearance of Lp(a) in Ldlr-/- mice was similar to wild-type 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 hour period. The kidney accounted for only a small fraction of tissue uptake (1.3 %). To test if apo(a) mediates the clearance of Lp(a) from plasma, we co-injected 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 clearance of Lp(a) in mice with the LDL receptor and apoE having no major roles. Our studies indicate that apo(a) is the primary ligand that mediates Lp(a) uptake and plasma clearance.
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