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.