The lipolysis-stimulated receptor (LSR) is a lipoprotein receptor primarily expressed in the liver and activated by free fatty acids. Antibodies inhibiting LSR functions showed that the receptor is a heterotrimer or tetramer consisting of 68-kDa (␣) and 56-kDa (␤) subunits associated through disulfide bridges. Screening of expression libraries with these antibodies led to identification of mRNAs derived by alternate splicing from a single gene and coding for proteins with molecular masses

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... ng that of LSR ␣ and ␤. Antibodies directed against a synthetic peptide of LSR ␣ and ␤ putative ligand binding domains inhibited LSR activity. Western blotting identified two liver proteins with the same apparent molecular mass as that of LSR ␣ and ␤. Transient transfections of LSR ␣ alone in Chinese hamster ovary cells increased oleate-induced binding and uptake of lipoproteins, while cotransfection of both LSR ␣ and ␤ increased oleate-induced proteolytic degradation of the particles. The ligand specificity of LSR expressed in cotransfected Chinese hamster ovary cells closely matched that previously described using fibroblasts from subjects lacking the low density lipoprotein receptor. LSR affinity is highest for the triglyceride-rich lipoproteins, chylomicrons, and very low density lipoprotein. We speculate that LSR is a rate-limiting step for the clearance of dietary triglycerides and plays a role in determining their partitioning between the liver and peripheral tissues. Chylomicrons transport, in plasma, dietary triglycerides (TG) 1 and liposoluble vitamins absorbed by the intestine after a meal (1). Lipoprotein lipase (LPL), which is anchored to the surface of capillary endothelium, hydrolyzes chylomicron TG into free fatty acids (FFA) that are targeted to the underlying muscles and adipose tissue. The residues of chylomicrons are then released from the endothelium and taken up by the liver. Both the low density lipoprotein (LDL) receptor and the LDL receptor-related protein (LRP) contribute to this process (2, 3). Studies using anti-LDL receptor antibodies or mice with a deficiency of the apoE gene suggest that the LDL receptor accounts for up to half of the clearance of chylomicrons (4, 5). However, human subjects deficient for the LDL receptor clear chylomicron remnants normally (6). In addition, mice with CRE-loxP-mediated selective disruption of the LRP gene in the liver are not hyperlipidemic (7) . If LRP-deficient mice are crossbred with LDL receptor-deficient mice, apoB48, the main chylomicron apolipoprotein, accumulates in the plasma (7) , but plasma TG concentrations in these mice are not dramatically increased. This is in contrast with the effect of the 39-kDa receptor-associated protein, a known inhibitor of LRP activity, which induces a massive increase of plasma TG and cholesterol when overexpressed in mice (8) . We have reported the characterization of a lipoprotein receptor that is inhibited by receptor-associated protein at concentrations similar to those achieved in the receptor-associated protein overexpression study (9). This receptor was originally identified by its binding of LDL in the presence of FFA and is hereafter referred to as the lipolysis-stimulated receptor (LSR). LSR binds apoB and apoE, displays the greatest affinity for TG-rich lipoprotein (chylomicrons and very low density lipoprotein (VLDL)), and does not bind ␤-VLDL isolated from subjects with type III hyperlipidemia (10, 11). Several characteristics of LSR suggest that it represents an important step for the clearance of chylomicrons. Indeed, LSR is expressed in the liver, and its activity is markedly increased in endocytic vesicles (10). LSR is inhibited by lactoferrin, a milk protein that, when injected intravenously, inhibits the uptake of chylomicrons by the liver (10, 12, 13) . Also, apoCIII inhibits the binding of triglyceride-rich lipoprotein chylomicrons and VLDL but not that of LDL to LSR (14), while apoCIII overexpression in mice induces profound hypertriglyceridemic effects (15). Finally, in rats, the apparent numbers of LSR expressed at the surface of hepatocytes correlate strongly and negatively with plasma TG levels measured in the postprandial stage (12). The limitations of this model are 2-fold. First, maximal activation of the receptor requires FFA at concentrations that exceed albumin-binding capacity. It is our hypothesis, as yet unproven that large amounts of FFA are released by hepatic lipase acting upon chylomicrons and VLDL directly in the environment that bathes the receptors (16). Second, the molecular characterization of the receptor remained incomplete and relied entirely on the identification of candidate proteins by ligand blotting in the presence of oleate (10, 12). We now report the cloning and characterization of a new gene, primarily expressed in the liver, which encodes a multimeric receptor that binds lipoproteins in the presence of FFA. We propose that LSR represents a rate-limiting step for the clearance of dietary TG from the circulation.