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] (Lpa]) catabolism are unknown. We examined the plasma clearance of Lpa] 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 Lpa] in Ldlr-/- mice was similar to that in wild-type mice and was only slightly accelerated in Apoe-/- mice. Hepatic uptake of Lpa] 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] (apoa]) mediates the clearance of Lpa] from plasma, we coinjected excess apoa] with labeled Lpa]. Apoa] acted as a potent inhibitor of Lpa] plasma clearance. Asialofetuin, a ligand of the asialoglycoprotein receptor, did not inhibit Lpa] clearance. In summary, the liver is the major organ accounting for the clearance of Lpa] in mice, with the LDL receptor and apolipoprotein E having no major roles. Our studies indicate that apoa] is the primary ligand that mediates Lpa] uptake and plasma clearance.