This paper describes a mechanism for degradation of low-density lipoprotein (LDL) in fibroblasts unable to synthesize the LDL receptor. In this cell line, long-chain free fatty acids (FFA) activated 125I-LDL uptake; unsaturated FFA were the most efficient. The first step of this pathway was the binding of LDL apoB to a single class of sites on the plasma membrane and was reversible in the presence of> 10 mM suramin. Binding equilibrium was achieved after a 60-90-min incubation at 37 C with 1 mM oleate; under these conditions, the apparent K¿ for 125I-LDL binding was 12.3 pg/mL. Both cholesterol-rich (LDL and| 8-VLDL) and triglyceride-rich (VLDL) lipoproteins, but not apoE-free HDL, efficiently competed with 125I-LDL for this FFA-induced binding site. After LDL bound to the cell surface, they were internalized and delivered to lysosomes; chloroquine inhibited subsequent proteolysis of LDL and thereby increased the cellular content of the particles. A physiological oleate to albumin molar ratio, ie, 1: 1 (25 µ oleate and 2 mg/mL albumin), was sufficient to significantly (p< 0.01) activate all three steps of this alternate pathway: for example, 644±217 (25 µ oleate) versus 33±57 (no oleate) ng of LDL/mg of cell protein was degraded after incubation (2 h, 37 C) with 50 µg/mL 125I-LDL. We speculate that this pathway could contribute to the clearance of both chylomicron remnants and LDL.

Ijow-density lipoproteins (LDL) 1 and chylomicron remnants bind with high affinity to the LDL receptor, which mediates endocytosis of both particles (Brown & Goldstein, 1986; Nagata et al., 1988). Besides this well-characterized receptor, less clearly delineated pathways significantly contribute to the removal of these lipoproteins (Shepherd et al., 1979; Goldstein & Brown, 1989). The issue of the mechanisms underlying these pathways has been addressed from two distinct perspectives:(1) a putative receptor for chylomicron remnants (Brown et al., 1991) and (2) a pathway forLDL receptor