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Journal of Lipid Research, Vol. 46, 2681-2691, December 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Lipoprotein [a] is cleared from the plasma primarily by the liver in a process mediated by apolipoprotein [a]

William J. Cain^1,*, 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
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA
Department of Pediatrics, Division of General Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA
^** Center for Liver, Digestive, and Metabolic Diseases, University of Groningen Medical Center, Groningen, The Netherlands
Pharmaceutical Division, Hoffmann-La Roche, Ltd., Basel, Switzerland

Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.M500249-JLR200

¹ To whom correspondence should be addressed. e-mail: will{at}udel.edu

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.

Supplementary key words kidney • tissue distribution • kinetics • LDL receptor • apolipoprotein E • asialoglycoprotein receptor

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