J. Clin. Invest. 108: 793–797 (2001). DOI: 10.1172/JCI200114011. designated SR-BII), and both are fatty acylated proteins that cluster in caveola-like cholesterol-rich lipid domains in cultured cells (see Febbraio et al., this Perspective series, ref. 10; see also ref. 11). Shortly after SR-BI was cloned, it was shown to bind to a variety of ligands other than AcLDL, including OxLDL, maleylated BSA, anionic phospholipids, apoptotic cells, and unmodified LDL and VLDL (11). The most striking and unexpected finding was that SR-BI binds HDL with high affinity (11, 13), raising the possibility, now confirmed, that SR-BI represented a longsought physiologically relevant HDL receptor. As is the case for the classic LDL receptor (LDLR), SRBI facilitates the cellular uptake of cholesterol (primarily in the form of cholesteryl esters) from the hydrophobic cores of lipoproteins by first mediating the binding of the lipoprotein to the outer surfaces of the cells. However, the mechanism of lipid uptake following lipoprotein binding for SR-BI differs markedly from that of the LDLR. The LDLR mediates endocytosis of the intact LDL particle via coated pits and vesicles, and its subsequent hydrolysis in lysosomes (14). SR-BI mediates the selective uptake of HDL’s cholesteryl esters (11, 13). Selective uptake involves efficient transfer to cells of the cholesteryl esters from the lipoprotein’s hydrophobic core, but not the apolipoprotein at the lipoprotein’s surface. It does not involve the sequential internalization of the intact lipoprotein particle and its subsequent degradation. Selective lipid uptake in vivo, primarily by the liver and steroidogenic tissues, was first identified almost 20 years ago by Glass et al. and Stein et al. during tissue clearance studies of plasma HDL differentially radiolabeled on both its lipid and protein components (reviewed in ref. 11).

SR-BI–mediated selective lipid uptake appears to be a two-step process, in which high-affinity lipoprotein binding is followed by receptor-mediated transfer of lipid from the lipoprotein particle to the cell membrane (reviewed in ref. 11). After lipid transfer, the lipiddepleted lipoprotein particle is released from the cells and re-enters the extracellular space. SR-BI can also mediate the bidirectional flux of unesterified cholesterol and phospholipids between HDL and cells, although the physiologic significance of SRBI–dependent cellular cholesterol efflux has not been established. SR-BI can function as an LDL receptor (binding and selective uptake) as well as an HDL receptor (reviewed in ref. 11). CD36 can also bind HDL and LDL, but it cannot efficiently mediate cholesteryl ester uptake (reviewed in ref. 11). The detailed molecular mechanism underlying SR-BI–mediated selective lipid uptake has not yet been elucidated. Several techniques have been used to show that there are distinct modes of binding and perhaps distinct binding sites for LDL and HDL on SR-BI (11, 15, 16). Strikingly, HDL competes effectively for the binding of LDL to SR-BI, whereas LDL can only partially compete for HDL binding to SR-BI (13). This phenomenon, termed “nonreciprocal cross-competition”(NRCC), has been documented in studies of SR-AI and SR-AII as well (17). In NRCC, one ligand efficiently competes for the binding of a second ligand whereas the second ligand fails to compete, or competes only partially, for the binding of the first. The observation of NRCC between ligands probably indicates that the receptor carries multiple binding sites with differing ligand binding properties. NRCC might also be observed under physiologically relevant experimental conditions (or, presumably, in vivo conditions) if ligand binding does not proceed to equilibrium. However it …