High density lipoprotein phospholipid composition is a major determinant of the bi-directional flux and net movement of cellular free cholesterol mediated by scavenger receptor BI

The role of high density lipoprotein (HDL) phospholipid in scavenger recept or BI (SR-BI)-mediated free cholesterol flux was examined by manipulating H DL, phosphatidylcholine and sphingomyelin content. Both phosphatidylcholine and sphingomyelin enrichment of HDL enhanced the net efflux of cholesterol from SR-BI-expressing COS-7 cells but by two different mechanisms. Phospha tidylcholine enrichment of HDL increased efflux, whereas sphingomyelin enri chment decreased influx of HDL cholesterol. Although similar trends were ob served in control (vector-transfected) COS-7 cells, SR-BI overexpression am plified the effects of phosphatidylcholine and sphingomyelin enrichment of HDL 25-and 2.8-fold, respectively. By using both phosphatidylcholine-enrich ed and phospholipase A(2)-treated HDL to obtain HDL with a graded phosphati dylcholine content, we showed that SR-BI-mediated cholesterol efflux was hi ghly correlated (r(2) = 0.985) with HDL phosphatidylcholine content. The ef fects of varying HDL phospholipid composition on SR-BI-mediated free choles terol flux were not correlated with changes in either the K-d or B-max valu es for high affinity binding to SR-BI. We conclude that SR-BI-mediated free cholesterol flux is highly sensitive to HDL phospholipid composition. Thus , factors that regulate cellular SR-BI expression and the local modificatio n of HDL phospholipid composition will have a large impact on reverse chole sterol transport.