Revised Manuscript Received November 8, 1993* abstract: This paper provides further characterization of a receptor that, in cells lacking the LDL receptor (FH fibroblasts), mediates lipoprotein binding, uptake, and degradation when incubatedwith oleate at concentrations not exceeding albumin binding capacity. This oleate-activated receptor is genetically distinct from the LDL receptor and is hereafter referred to as the lipolysis-stimulated receptor (LSR). Its apparent affinity was higher for triglyceride-rich lipoproteins (chylomicrons, VLDL) and for lipid emulsions supplemented with recombinant apoE, thanfor LDL which contains solely apoB. In contrast, VLDL isolated from a Type III hyperlipidemic patient (apoE2/2 phenotype) failed to bind to the LSR. Five lines of evidence indicated that the LSR is distinct from the LDL receptor-related protein (LRP):(1) the LRP ligand, a2-macroglobulin-methylamine (a2-MG*), did not bind to the oleate-induced LDL binding site;(2) oleate had no effect on the binding of a2-MG* to LRP;(3) the LRP-associated protein, RAP, which inhibits LRP, had no effect on the LSR;(4) binding of lipoproteins to LSR was independent of Ca2+; and (5) LSR activity resolved as two proteins smaller than LRP (apparent molecular masses as determined by ligand blots: 115 and 85 kDa). That LSR provides a new candidate receptor contributing to the clearance of chylomicron remnants (CMR) is supported by the observation thatLSR was inhibited by lactoferrin, a milk protein that delays CMR clearance when injected in vivo. Furthermore, inprimary cultures of rat hepatocytes, oleate stimulated binding, uptake, and degradation of LDL with kineticcharacteristics similar to that of LSR expressed in FH fibroblasts. LDL binding to LSR was also demonstrated in isolated liver membranes. Membranes from liver endocyticorganelles showed marked (10-15-fold) enrichment in LSR activity when compared to totalliver membranes; virtually no LSR activity was detected in liver mitochondrial membranes. We propose that LSR’s primary function is to mediate the clearance of intestinally derived triglyceride-rich lipoproteins and that free fatty acids produced by the action of lipolytic enzymes on these particles are the signals activating this receptor.

Chylomicrons (CM) 1 are the lipoproteins produced by the intestine after a meal. Upon entering the circulation, CM-triglycerides (TG) are hydrolyzed by lipoprotein and hepatic lipases (Havel & Kane, 1975). This process takes place in the capillaries of muscle and adipose tissue as well as at the surface of fenestrated liver endothelium. CM lipolysis leads to the production of remnants which enter the space of Disse and are subsequently removed by hepatocytes (Sherrill & Dietschy, 1978).