Use of monoclonal anti-receptor antibodies to probe the expression of the low density lipoprotein receptor in tissues of normal and Watanabe Heritable Hyperlipidemic rabbits

Watanabe Heritable Hyperlipidemic (WHHL) rabbits, like humans with familial hypercholesterolemia, have a genetic defect in the low density lipoprotein (LDL) receptor. WHHL fibroblasts produce a low molecular weight precursor form of the receptor that is not glycosylated normally and is not transported to the cell surface at a normal rate. In the current studies, we have used a monoclonal antibody that reacts with the rabbit LDL receptor to extend these findings to intact rabbits. We have made the following observations: (a) In normal rabbits the liver and adrenal glands synthesize high molecular weight mature LDL receptors like those in fibroblasts. (b) In WHHL rabbits the adrenals express only the low molecular weight receptor precursor, and the liver expresses no detectable receptors. (c) When injected intravenously, the radioiodinated anti-LDL receptor monoclonal antibody is cleared from plasma 6-10-fold faster in normal than in WHHL rabbits, with specific uptake demonstrable in livers and adrenals of normal but not WHHL rabbits. The latter findings raise the general possibility that the total number of cell surface receptors expressed by an animal or human in vivo can be estimated by measuring the rate of clearance of an intravenously injected monoclonal antibody directed against the receptor of interest.