Relative roles of the LDL receptor, the LDL receptor-like protein, and hepatic lipase in chylomicron remnant removal by the liver.
Studies were carried out in mice utilizing inhibitors of several cell surface molecules to evaluate their relative roles in chylomicron remnant removal. Anti-LDL receptor antibody inhibited approximately 45% of rapid remnant removal from plasma, prolonged their half life (63 s to 115 s) and reduced hepatic uptake by 45%. Receptor-associated protein (RAP) (1 mg/mouse), a high affinity inhibitor of the LDL receptor-related protein (LRP) and a low affinity inhibitor of the LDL receptor decreased remnant removal approximately 55%, prolonged the half life from 63 s to 230 s, and reduced hepatic uptake by 70%. RAP, but not anti-LDL receptor antibody, inhibited splenic uptake. With both injected together, an incremental effect was seen; plasma removal decreased 60%, T1/2 increased to 290 s, and hepatic uptake decreased by 80%. Thus, it is likely that virtually all of the very rapid removal of remnants from the plasma by the liver requires the presence of at least one of these members of the LDL receptor family. Anti-hepatic lipase antibody caused a small but significant delay in remnant removal from plasma and a larger decrease in hepatic uptake (22.5%). It doubled adrenal uptake. The anti-hepatic lipase antibody was not additive with either the anti-LDL receptor antibody or RAP. Anti-rat hepatic lipase antibody did not inhibit lipolysis by mouse hepatic lipase, suggesting that lipolysis is not the way hepatic lipase enhances remnant uptake. Hepatic lipase bound to remnants to a greater degree than it bound to other lipoproteins. Together these data suggest that hepatic lipase may serve as a binding site for chylomicron remnants, thereby enhancing their affinity for the liver surface, and thus removal by the proteins of the LDL receptor family. Other molecules may also play a role in removal from the circulation under conditions where the LDL receptor family receptors are absent or occupied.
de Faria
E
E
Research Institute, Palo Alto Medical Foundation, CA 94305, USA.
Fong
L G
LG
Komaromy
M
M
Cooper
A D
AD
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002914:Chylomicrons / Q000378:metabolism*; D005260:Female; D008049:Lipase / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D051381:Rats; D011971:Receptors, Immunologic / Q000378:metabolism*; D011973:Receptors, LDL / Q000187:drug effects / Q000378:metabolism*
D000906:Antibodies; D002914:Chylomicrons; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D008049:Lipase