Abstract
Scavenger receptor, class B, type I (SR-BI) is a cell-surface glycoprotein that mediates selective uptake of high density lipoprotein cholesteryl ester (CE) without the concomitant uptake and degradation of the particle. We have investigated the endocytic and selective uptake of low density lipoprotein (LDL)-CE by SR-BI using COS-7 cells transiently transfected with mouse SR-BI. Analysis of lipoprotein uptake data showed a concentration-dependent LDL-CE-selective uptake when doubly labeled LDL particles were incubated with SR-BI-expressing COS-7 cells. In contrast to vector-transfected cells, SR-BI-expressing COS-7 cells showed marked increases in LDL cell association and CE uptake by the selective uptake pathway, but only a modest increase in CE uptake by the endocytic pathway. SR-BI-mediated LDL-CE-selective uptake exceeded LDL endocytic uptake by 50-100-fold. SR-BI-mediated LDL-CE-selective uptake was not inhibited by the proteoglycan synthesis inhibitor, p-nitrophenyl-beta-D-xylopyranoside or by the sulfation inhibitor sodium chlorate, indicating that SR-BI-mediated LDL-CE uptake occurs independently of LDL interaction with cell-surface proteoglycan. Analyses with subclones of Y1 adrenocortical cells showed that LDL-CE-selective uptake was proportional to the level of SR-BI expression. Furthermore, antibody directed to the extracellular domain of SR-BI blocked LDL-CE-selective uptake in adrenocortical cells. Thus, in cells that normally express SR-BI and in transfected COS-7 cells SR-BI mediates the efficient uptake of LDL-CE via the selective uptake mechanism. These results suggest that SR-BI may influence the metabolism of apoB-containing lipoproteins in vivo by mediating LDL-CE uptake into SR-BI-expressing cells.
Highlights
Scavenger receptor class B, type I (SR-BI)1 is a cell-surface glycoprotein of molecular mass ϳ82 kDa that binds HDL, LDL, modified LDL, and VLDL (1– 4)
SR-BI-mediated LDL-CE-selective Uptake—In order to determine whether mSR-BI mediates the selective uptake of LDL-CE, COS-7 cells transfected with vector or with vector expressing mSR-BI were incubated for 4 h with 125I,3H-hLDL after which LDL cell association, LDL-CE-selective uptake, and LDL-CE endocytic uptake (Fig. 1) were measured
SR-BI has been characterized as an HDL receptor (1, 10), its ability to bind LDL particles suggested that it might play a role in LDL metabolism
Summary
Scavenger receptor class B, type I (SR-BI) is a cell-surface glycoprotein of molecular mass ϳ82 kDa that binds HDL, LDL, modified LDL, and VLDL (1– 4). Mice carrying an induced SR-BI mutation that reduced hepatic SR-BI expression levels by 50% showed a similar reduction in hepatic HDL-CE-selective uptake (12) These studies with reduced SR-BI expression are complemented by studies in which hepatic SR-BI is overexpressed by either an adenovirus vector (13) or via a transgene (14). In one study with transgenic mice, aortic root lesions were reduced by 80% in heterozygous LDL receptor-deficient mice overexpressing hepatic SR-BI when fed a high fat-, cholesterol-, and bile salt-containing diet (19). Mice deficient in both SR-BI and apoE show accelerated atherosclerotic lesion development in the aortic root region and an increased accumulation of VLDL-sized particles (20) These data indicate that hepatic SR-BI can influence, directly or indirectly, the metabolism of apoB-containing particles and the development of arterial lesions. Are the observed effects indirect via changes in HDL metabolism or direct via processing of LDL particles by SR-BI? Second, if SR-BI can process LDL particles, does it do so by the selective uptake pathway or does SR-BI mediate
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