Abstract
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 mM), 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, 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, T. J. F.,
J. T. Shaw, F. A. Jaipuri, Z. Maliga, J. L. Duffner, A. N.
Koehler, and M. Krieger. Influence of HDL-cholesterolelevating
drugs on the in vitro activity of the HDL receptor
SR-BI.
