Abstract
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 been reported, and studies in transgenic mice have suggested that apoA-II is pro-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 investigated the abilities of apoA-I and apoA-II to mediate SR-BI-specific binding and selective uptake of cholesterol ester using reconstituted HDLs (rHDLs) that were homogeneous in size and apolipoprotein content. Particles were labeled in the protein (with (125)I) and in the lipid (with [(3)H]cholesterol ether) components and SR-BI-specific events were analyzed in SR-BI-transfected Chinese hamster ovary cells. At 1 microg/ml apolipoprotein, SR-BI-mediated cell association of palmitoyloleoylphosphatidylcholine-containing AI-rHDL was significantly greater (3-fold) than that of AI/AII-rHDL, with a lower K(d) and a higher B(max) for AI-rHDL as compared with AI/AII-rHDL. Unexpectedly, selective cholesterol ester uptake from AI/AII-rHDL was not compromised compared with AI-rHDL, despite decreased binding. The efficiency of selective cholesterol ester uptake in terms of SR-BI-associated rHDL was 4-5-fold 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 selective cholesterol ester uptake with an efficiency dependent on the composition of the ligand. ApoA-II decreases binding but increases selective uptake. These findings show that apoA-II can exert a significant influence on selective cholesterol ester uptake by SR-BI and may consequently influence the metabolism and function of HDL, as well as the pathway of reverse cholesterol transport.
Highlights
The scavenger receptor, SR-BI, plays a major role in HDL metabolism, binding HDL and mediating selective lipid uptake from HDL into the liver and steroidogenic cells [23,24,25,26]
To assess rHDL binding to SR-BI, DPPC-containing particles were first iodinated with 125I and incubated with CHO cells transfected with human SR-BI (CHO-SRBI)
SR-BI mediates the selective uptake of cholesteryl ester (CE) from HDL without uptake and subsequent degradation of HDL apolipoproteins [23]
Summary
Vol 276, No 19, Issue of May 11, pp. 15832–15839, 2001 Printed in U.S.A. Apolipoprotein A-II Modulates the Binding and Selective Lipid Uptake of Reconstituted High Density Lipoprotein by Scavenger Receptor BI*. In this study we investigated the abilities of apoA-I and apoA-II to mediate SR-BI-specific binding and selective uptake of cholesterol ester using reconstituted HDLs (rHDLs) that were homogeneous in size and apolipoprotein content. The scavenger receptor, SR-BI, plays a major role in HDL metabolism, binding HDL and mediating selective lipid uptake from HDL into the liver and steroidogenic cells [23,24,25,26]. SR-BI scavenger receptor class B, type I; CHO, Chinese hamster ovary; BSA, bovine serum albumin; rHDL, reconstituted HDL; DPPC, dipalmitoylphosphatidyl choline; POPC, L-␣-palmitoyloleolyl-phosphatidylcholine; CE, cholesterol ester. ApoA-II modulation of SR-BI activity, may contribute to the reported differences in function and metabolism between LpA-I and LpA-I/A-II
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