Journal
JOURNAL OF LIPID RESEARCH
Volume 46, Issue 12, Pages 2681-2691Publisher
ELSEVIER
DOI: 10.1194/jlr.M500249-JLR200
Keywords
kidney; tissue distribution; kinetics; LDL receptor; apolipoprotein E; asialoglycoprotein receptor
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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.
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