A COMPARISON OF THE ROLES OF THE LOW-DENSITY-LIPOPROTEIN (LDL) RECEPTOR AND THE LDL RECEPTOR-RELATED PROTEIN-ALPHA-2-MACROGLOBULIN RECEPTORIN CHYLOMICRON REMNANT REMOVAL IN THE MOUSE IN-VIVO

Two cell surface molecules, the low density lipoprotein (LDL) receptor and the LDL receptor-related protein (LRP)/alpha2-macroglobulin recep tor, have been found to have a role in the removal of apoE-rich lipopr oteins. To further study this process and to assess the relative contr ibutions of these proteins to the removal of chylomicron remnants, we used an anti-LDL receptor antibody, activated alpha2-macroglobulin and the 39-kDa receptor-associated protein (RAP) as inhibitors of chylomi cron remnant removal in intact mice. The advantage of this study is th at we were able to use the same litters of animals and batches of lipo protein for the experiment. In cultured Chinese hamster ovary cells, t he anti-LDL receptor antibody inhibited remnant uptake and degradation about 80% as well as did unlabeled remnants. It did not affect activa ted alpha2-macroglobulin uptake or degradation. Activated alpha2-macro globulin did not inhibit remnant uptake in normal cells but is reporte d to block uptake in cells that lack LDL receptors. Chylomicron remnan ts blocked activated alpha2-macroglobulin uptake as effectively as unl abeled activated alpha2-MaCroglobulin. This confirmed that the two lig ands are cross-competitors but suggests that the LDL receptor is the p rimary mediator of remnant uptake in cultured cells that express the L DL receptor. In vivo, pretreatment with the anti-LDL receptor antibody decreased remnant uptake 5 min after injection by one-third. The anti body did not affect the removal of activated alpha2-macroglobulin. Act ivated alpha2-macroglobulin had a small, but reproducible effect on re mnant removal, decreasing it by about 7% at 5 min. Injection of chylom icron remnants affected activated alpha2-macroglobulin removal slightl y. A similar pattern, but somewhat greater effect was seen on the hepa tic uptake of the ligands. Anti-LDL receptor antibody reduced chylomic ron remnant uptake by about half, and activated alpha2-macroglobulin r educed it by about 15%. Studies with RAP provided results generally si milar to those with activated alpha2-macroglobulin, although RAP appea rs to bind to a site not recognized by either remnants or activated al pha2-macroglobulin in addition to sharing a site with these ligands. T ogether, these results add support for the hypothesis that, although b oth receptors can play a role in chylomicron remnant removal, in the n ormal mouse in vivo the LDL receptor plays a substantially greater rol e, making the role of the LRP difficult to appreciate. The same is tru e in cells that express LDL receptors. However, the persistent, fairly rapid clearance of these particles in the presence of both competitor s suggests that there is either a site on the LRP that is not blocked by activated alpha2-macroglobulin or RAP or there is another, perhaps non-endocytic mechanism for their removal from plasma as well.