The Class B type I scavenger receptor I (SR-BI) is a physiologically relevant high density lipoprotein (HDL) receptor that can mediate selective cholesteryl ester (CE) uptake by cells. Direct interaction of apolipoprotein E (apoE) with this receptor has never been demonstrated, and its implication in CE uptake is still controversial. By using a human adrenal cell line (NCI-H295R), we have addressed the role of apoE in binding to SR-BI and in selective CE uptake from lipoproteins to cells. This cell line does not secrete apoE and SR-BI is its major HDL-binding protein. We can now provide evidence that 1) free apoE is a ligand for SR-BI, 2) apoE associated to lipids or in lipoproteins does not modulate binding or CE-selective uptake by the SR-BI pathway, and 3) the direct interaction of free apoE to SR-BI leads to an increase in CE uptake from lipoproteins of both low and high densities. We propose that this direct interaction could modify SR-BI structure in cell membranes and potentiate CE uptake.The Class B type I scavenger receptor I, SR-BI, 1 binds HDL and mediates the selective uptake of HDL cholesteryl esters (CE) in cultured cells (1). Another property of the Class B scavenger receptor, shared with CD 36, is to bind either native (2, 3) or modified lipoproteins (acetylated or oxidized (3-5)). They are also the first defined receptors to be able to specifically bind anionic but not cationic or zwitterionic liposomes (6). However CD 36 is less efficient than SR-BI in promoting CE-HDL uptake from native lipoproteins to cells (7).There are probably different binding sites on SR-BI. HDL compete for the binding of LDL to SR-BI but LDL poorly inhibit the binding of HDL, and there is no reciprocal cross-competition between these two ligands (1, 8). The study of several mutants of SR-BI also supports for the proposal that the interaction of SR-BI with HDL differs from that with LDL (9).Apolipoproteins (apo) AI, AII, and CIII of HDL either associated with lipids or in lipid free forms can directly mediate their binding to SR-BI (10). Williams et al. (11) demonstrated that SR-BI can interact with multiple sites in apoAI and identified the Class A amphipathic ␣-helix as a recognition motif. The specific role of apoAI in the delivery of cholesterol to adrenal cells was clearly demonstrated in mice deficient either in apoAI or apoAII (12). We have demonstrated, in a human adrenal cell line, that apoAII, which binds SR-BI with high affinity, can act as an antagonist of apoAI in CE-HDL uptake (13).ApoE is a constituent of trigyceride-rich lipoproteins and is essential for the receptor-mediated uptake of their remnants (14) and for their catabolism by pathways involving heparansulfate proteoglycans (15). ApoE deficiency in mice leads to impaired catabolism of these remnants and increased atherosclerotic lesions (for review, see Ref. 16). Direct interaction of apoE with SR-BI has never been demonstrated, and its implication in CE uptake is still controversial.It was previously shown that HDL binds murine SR-BI (1), human SR...

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