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Journal of Lipid Research, Vol. 48, 1832-1845, August 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Influence of HDL-cholesterol-elevating drugs on the in vitro activity of the HDL receptor SR-BI

Thomas J. F. Nieland^1,*, Jared T. Shaw, Firoz A. Jaipuri, Zoltan Maliga^2,, Jay L. Duffner, Angela N. Koehler and Monty Krieger^3,*

^* Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139
Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142
Program in Biophysics, Harvard University, Boston, MA 02115

Published, JLR Papers in Press, May 28, 2007.

¹ Present address of T. J. F. Nieland: Johns Hopkins Medical Institute, Department of Neuroscience, 725 North Wolfe Street, Baltimore, MD 21205.

² Present address of Z. Maliga: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, Dresden 01307, Germany.

³ To whom correspondence should be addressed. e-mail: krieger{at}mit.edu

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 (IC₅₀ 1 µM), 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 , 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.

Supplementary key words niacin • fibrates • HDL376 • lipoprotein metabolism • fenofibrate • structure-activity relationship • scavenger receptor class B type I • high density lipoprotein

Abbreviations: ACTH, adrenocorticotropic hormone; BLT-1, blocker of lipid transport-1; CE, cholesteryl oleyl ether; CETP, cholesteryl ester transfer protein; DiI, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate; FAF, fatty acid-free; FF, fenofibrate; FFA, fenofibric acid; PBS+, PBS containing 1 mM MgCl₂ and 0.1 mM CaCl₂; PPAR, peroxisome proliferator-activated receptor ; SEM, standard error of the mean; SR-BI, scavenger receptor class B type I

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