title: Discovery of chemical inhibitors of the selective transfer of lipids mediated by the HDL receptor SR-BI.
abstract: The high-density lipoprotein (HDL) receptor, scavenger receptor, class B, type I (SR-BI), mediates both the selective uptake of lipids, mainly cholesterol esters, from HDL to cells and the efflux of cholesterol from cells to lipoproteins. The mechanism underlying these lipid transfers is distinct from classic receptor-mediated endocytosis, but it remains poorly understood. To investigate SR-BI's mechanism of action and in vivo function, we developed a high-throughput screen to identify small molecule inhibitors of SR-BI-mediated lipid transfer in intact cells. We identified five compounds that in the low nanomolar to micromolar range block lipid transport (BLTs), both selective uptake and efflux. The effects of these compounds were highly specific to the SR-BI pathway, because they didn't interfere with receptor-mediated endocytosis or with other forms of intracellular vesicular traffic. Surprisingly, all five BLTs enhanced, rather than inhibited, HDL binding by increasing SR-BI's binding affinity for HDL (decreased dissociation rates). Thus, the BLTs provide strong evidence for a mechanistic coupling between HDL binding and lipid transport and may serve as a starting point for the development of pharmacologically useful modifiers of SR-BI activity and, thus, HDL metabolism.
authors.affiliation: Department of Cell Biology, Harvard Medical School, and Center for Blood Research, Boston, MA 02115-5701, USA.
authors.forename: Thomas J F
authors.initials: TJ
authors.lastname: Nieland
authors.forename: Marsha
authors.initials: M
authors.lastname: Penman
authors.forename: Limor
authors.initials: L
authors.lastname: Dori
authors.forename: Monty
authors.initials: M
authors.lastname: Krieger
authors.forename: Tomas
authors.initials: T
authors.lastname: Kirchhausen
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018955:CD36 Antigens / Q000187:drug effects* / Q000378:metabolism; D016466:CHO Cells / Q000378:metabolism; D002232:Carbocyanines / Q000378:metabolism; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D002966:Clathrin / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D004336:Drug Antagonism; D004705:Endocytosis / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D006367:HeLa Cells / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008970:Molecular Weight; D011485:Protein Binding; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D051122:Scavenger Receptors, Class B; D013379:Substrate Specificity
chemical_list: D018955:CD36 Antigens; D002232:Carbocyanines; D002966:Clathrin; D005456:Fluorescent Dyes; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D011993:Recombinant Fusion Proteins; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C024286:3,3'-dioctadecylindocarbocyanine; D000324:Adrenocorticotropic Hormone