Apolipoprotein A-II modulates the binding and selective lipid uptake of reconstituted high density lipoprotein by scavenger receptor BI

High density lipoprotein (HDL) represents a mixture of particles containing either apoA-I and apoA-II (LpA-I/A-II) or apoA-I without apoA-II (LpA-I). Differences in the function and metabolism of LpA-I and LpA-I/A-II have bee n reported, and studies in transgenic mice have suggested that apoA-II is p ro-atherogenic in contrast to anti-atherogenic apoA-I. The molecular basis for these observations is unclear. The scavenger receptor BI (SR-BI) is an HDL receptor that plays a key role in HDL metabolism. In this study we inve stigated the abilities of apoA-I and apoA-II to mediate SR-BI-specific bind ing and selective uptake of cholesterol ester using reconstituted HDLs (rHD Ls) that were homogeneous in size and apolipoprotein content. Particles wer e labeled in the protein (with I-125) and in the lipid (with [H-3]cholester ol ether) components and SR-BI-specific events were analyzed in SR-BI-trans fected Chinese hamster ovary cells. At 1 mug/ml apolipoprotein, SR-BI-media ted cell association of palmitoyloleoylphosphatidylcholine-containing AI-rH DL was significantly greater (3-fold) than that of AI/AII-rHDL, with a lowe r K-d and a higher B-max for AI-rHDL as compared with AI/AII-rHDL. Unexpect edly, selective cholesterol ester uptake from AI/AII-rHDL was not compromis ed compared with AI-rHDL, despite decreased binding. The efficiency of sele ctive cholesterol ester uptake in terms of SR-BI-associated rHDL was 4-5-fo ld greater for AI/AII-rHDL than AI-rHDL. These results are consistent with a two-step mechanism in which SR-BI binds ligand and then mediates selectiv e cholesterol eater uptake with an efficiency dependent on the composition of the ligand, ApoA-II decreases binding but increases selective uptake. Th ese findings show that apoA-II can exert a significant influence on selecti ve cholesterol ester uptake by SR-BI and may consequently influence the met abolism and function of HDL, as well as the pathway of reverse cholesterol transport.