The efficient cellular uptake of high density lipoprotein lipids via scavenger receptor class B type I requires not only receptor-mediated surface binding but also receptor-specific lipid transfer mediated by its extracellular domain.

The class B type I scavenger receptor, (SR-BI), is a member of the CD36 superfamily of proteins and is a physiologically relevant, high affinity cell surface high density lipoprotein (HDL) receptor that mediates selective lipid uptake. The mechanism of selective lipid uptake is fundamentally different from that of classic receptor-mediated uptake via coated pits and vesicles (e.g. the low density lipoprotein receptor pathway) in that it involves efficient transfer of the lipids, but not the outer shell proteins, from HDL to cells. The abilities of SR-BI and CD36, both of which are class B scavenger receptors, to bind HDL and mediate cellular uptake of HDL-associated lipid when transiently expressed in COS cells were examined. For these experiments, the binding of HDL to cells was assessed using either 125I- or Alexa (a fluorescent dye)-HDL in which the apolipoproteins on the surface of the HDL particles were covalently modified. Lipid transfer was measured using HDL noncovalently labeled by the fluorescent lipid 1,1'-dioctadecyl-3,3, 3',3'-tetramethylindocarbocyanine perchlorate. Although both mSR-BI and human CD36 (hCD36) could mediate the binding of HDL in a punctate pattern across the surfaces of cells, only mSR-BI efficiently mediated the transfer of lipid to the cells. Analysis of point mutants established that the major sites of fatty acylation of mSR-BI are Cys462 and Cys470 and that fatty acylation is not required for receptor clustering, HDL binding, or efficient lipid transfer. Generation of mSR-BI/hCD36 domain swap chimeras showed that the differences in lipid uptake activities between mSR-BI and hCD36 were not due to differences between their two sets of transmembrane and cytoplasmic domains but rather result from differences in their large extracellular loop domains. These results show that high affinity binding to a cell surface receptor is not sufficient to ensure efficient cellular lipid uptake from HDL. Thus, SR-BI-mediated binding combined with SR-BI-dependent facilitated transfer of lipid from the HDL particle to the cell appears to be the most likely mechanism for the bulk of the selective uptake of cholesteryl esters from HDL to the liver and steroidogenic tissues.

Scavenger receptor BI--a cell surface receptor for high density lipoprotein.

The receptor-mediated transfer of lipids between cells and lipoproteins plays an important role in lipoprotein metabolism and cardiovascular disease. Although there have been many valuable studies of HDL binding to tissues, cells and membranes, and of the potential role of such binding in the transport of lipids between HDL and cells, much less is known about HDL receptors than about receptors for other lipoproteins (e.g. LDL, chylomicrons, vitellogenin). Here we review recent studies of the class B, type I scavenger receptor, which appears to be a physiologically relevant, cell surface HDL receptor that mediates the selective uptake of lipids by cells.

Murine SR-BI, a high density lipoprotein receptor that mediates selective lipid uptake, is N-glycosylated and fatty acylated and colocalizes with plasma membrane caveolae.

The class B, type I scavenger receptor, SR-BI, was the first molecularly well defined cell surface high density lipoprotein (HDL) receptor to be described. It mediates transfer of lipid from HDL to cells via selective lipid uptake, a mechanism distinct from receptor-mediated endocytosis via clathrin-coated pits and vesicles. SR-BI is expressed most abundantly in steroidogenic tissues (adrenal gland, ovary), where trophic hormones coordinately regulate its expression with steroidogenesis, and in the liver, where it may participate in reverse cholesterol transport. Here we have used immunochemical methods to study the structure and subcellular localization of murine SR-BI (mSR-BI) expressed either in transfected Chinese hamster ovary cells or in murine adrenocortical Y1-BS1 cells. mSR-BI, an approximately 82-kDa glycoprotein, was initially synthesized with multiple high mannose N-linked oligosaccharide chains, and some, but not all, of these were processed to complex forms during maturation of the protein in the Golgi apparatus. Metabolic labeling with [3H]palmitate and [3H]myristate demonstrated that mSR-BI was fatty acylated, a property shared with CD36, another class B scavenger receptor, and other proteins that concentrate in specialized, cholesterol- and glycolipid-rich plasma membrane microdomains called caveolae. OptiPrep density gradient fractionation of plasma membranes established that mSR-BI copurified with caveolin-1, a constituent of caveolae; and immunofluorescence microscopy demonstrated that mSR-BI colocalized with caveolin-1 in punctate microdomains across the surface of cells and on the edges of cells. Thus, mSR-BI colocalizes with caveolae, and this raises the possibility that the unique properties of these specialized cell surface domains may play a critical role in SR-BI-mediated transfer of lipids between lipoproteins and cells.