J. Lipid Res.  Neurobiology of Lipids (ISSN1683-5506)
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Originally published In Press as doi:10.1194/jlr.M700209-JLR200 on May 28, 2007

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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. Nieland1,*, Jared T. Shaw{dagger}, Firoz A. Jaipuri{dagger}, Zoltan Maliga2,§, Jay L. Duffner{dagger}, Angela N. Koehler{dagger} and Monty Krieger3,*

* Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139
{dagger} 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 {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.

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{alpha}, peroxisome proliferator-activated receptor {alpha}; SEM, standard error of the mean; SR-BI, scavenger receptor class B type I


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