Scavenger receptor class B, type I-mediated [H-3]cholesterol efflux to high and low density lipoproteins is dependent on lipoprotein binding to the receptor

The murine scavenger receptor class B, type I (mSR-BI) is a receptor for hi gh density lipoprotein (HDL), low density lipoprotein (LDL), and acetylated LDL (AcLDL). It mediates selective uptake of lipoprotein lipid and stimula tes efflux of [H-3]cholesterol to lipoproteins. SR-BI-mediated [H-3]cholest erol efflux was proposed to be independent of ligand binding. In this study , using anti-mSR-BI antibody KKB-1 and two mSR-BI mutants with altered liga nd binding properties, we demonstrated that SR-BI-mediated [H-3]cholesterol efflux to lipoproteins was correlated with ligand binding and lipid uptake activities of the receptor. The KKB-1 antibody, which blocked lipoprotein binding without substantially altering the cholesterol oxidase-accessible c ellular [H-3]cholesterol, also blocked [H-3]cholesterol efflux to HDL and L DL. One of the SR-BI mutants, which has a double substitution of arginines for glutamines at positions 402 and 418 (Q402R/Q418R), exhibited a high lev el of LDL binding and lipid uptake from LDL, but lost most of the correspon ding HDL receptor activity. This mutant could mediate efficient [H-3]choles terol efflux to LDL, but not to HDL. Another mutant, M158R, with an arginin e in place of methionine at position 158, exhibited reduced HDL and LDL rec eptor activities, but apparently normal AcLDL receptor activity. This mutan t could mediate efficient [H-3]cholesterol efflux to AcLDL, but not to HDL or LDL. These results suggest that SR-BI-stimulated [H-3]cholesterol efflux to lipoproteins critically depends on ligand binding to this receptor and raise the possibility that the mechanisms of selective lipid uptake and [H- 3]cholesterol efflux may be intimately related.