Cross-inhibition of SR-BI- and ABCA1-mediated cholesterol transport by the small molecules BLT-4 and glyburide.
Scavenger receptor class B type I (SR-BI) and ABCA1 are structurally dissimilar cell surface proteins that play key roles in HDL metabolism. SR-BI is a receptor that binds HDL with high affinity and mediates both the selective lipid uptake of cholesteryl esters from lipid-rich HDL to cells and the efflux of unesterified cholesterol from cells to HDL. ABCA1 mediates the efflux of unesterified cholesterol and phospholipids from cells to lipid-poor apolipoprotein A-I (apoA-I). The activities of ABCA1 and other ATP binding cassette superfamily members are inhibited by the drug glyburide, and SR-BI-mediated lipid transport is blocked by small molecule inhibitors called BLTs. Here, we show that one BLT, [1-(2-methoxy-phenyl)-3-naphthalen-2-yl-urea] (BLT-4), blocked ABCA1-mediated cholesterol efflux to lipid-poor apoA-I at a potency similar to that for its inhibition of SR-BI (IC(50) approximately 55-60 microM). Reciprocally, glyburide blocked SR-BI-mediated selective lipid uptake and efflux at a potency similar to that for its inhibition of ABCA1 (IC(50) approximately 275-300 microM). As is the case with BLTs, glyburide increased the apparent affinity of HDL binding to SR-BI. The reciprocal inhibition of SR-BI and ABCA1 by BLT-4 and glyburide raises the possibility that these proteins may share similar or common steps in their mechanisms of lipid transport.
Nieland
Thomas J F
TJ
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Chroni
Angeliki
A
Fitzgerald
Michael L
ML
Maliga
Zoltan
Z
Zannis
Vassilis I
VI
Kirchhausen
Tomas
T
Krieger
Monty
M
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D018955:CD36 Antigens; D002784:Cholesterol / Q000378:metabolism*; D005905:Glyburide / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008075:Lipoproteins, HDL / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology*
C496792:(1-(2-methoxy-phenyl)-3-naphthalen-2-yl-urea); C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D018955:CD36 Antigens; D008075:Lipoproteins, HDL; D009281:Naphthalenes; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D014508:Urea; D002784:Cholesterol; D005905:Glyburide