Influence of HDL-cholesterol-elevating drugs on the in vitro activity of the HDL receptor SR-BI.
Treatment of atherosclerotic disease often focuses on reducing plasma LDL-cholesterol or increasing plasma HDL-cholesterol. We examined in vitro the effects on HDL receptor [scavenger receptor class B type I (SR-BI)] activity of three classes of clinical and experimental plasma HDL-cholesterol-elevating compounds: niacin, fibrates, and HDL376. Fenofibrate (FF) and HDL376 were potent (IC(50) approximately 1 microM), direct inhibitors of SR-BI-mediated lipid transport in cells and in liposomes reconstituted with purified SR-BI. FF, a prodrug, was a more potent inhibitor of SR-BI than an activator of peroxisome proliferator-activated receptor alpha, a target of its active fenofibric acid (FFA) derivative. Nevertheless, FFA, four other fibrates (clofibrate, gemfibrozil, ciprofibrate, and bezafibrate), and niacin had little, if any, effect on SR-BI, suggesting that they do not directly target SR-BI in vivo. However, similarities of HDL376 treatment and SR-BI gene knockout on HDL metabolism in vivo (increased HDL-cholesterol and HDL particle sizes) and structure-activity relationship analysis suggest that SR-BI may be a target of HDL376 in vivo. HDL376 and other inhibitors may help elucidate SR-BI function in diverse mammalian models and determine the therapeutic potential of SR-BI-directed pharmaceuticals.
Nieland
Thomas J F
TJ
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Shaw
Jared T
JT
Jaipuri
Firoz A
FA
Maliga
Zoltan
Z
Duffner
Jay L
JL
Koehler
Angela N
AN
Krieger
Monty
M
D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000378:metabolism*; D002995:Clofibric Acid / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D011345:Fenofibrate / Q000494:pharmacology; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D018110:Receptors, Lipoprotein / Q000378:metabolism*; D051122:Scavenger Receptors, Class B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013890:Thiourea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
D000924:Anticholesteremic Agents; D008076:Cholesterol, HDL; D008075:Lipoproteins, HDL; D018110:Receptors, Lipoprotein; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; C031616:high density lipoprotein receptors; D002995:Clofibric Acid; C108967:SDZ HDL 376; D013890:Thiourea; D011345:Fenofibrate