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 (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

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 (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

Mannose-Functionalized “Pathogen-like” Polyanhydride Nanoparticles Target C-Type Lectin Receptors on Dendritic Cells

Targeting pathogen recognition receptors ondendritic cells (DCs) offers the advantage of triggering specificsignaling pathways to induce a tailored and robust immuneresponse. In this work, we describe a novel approach to targetedantigen delivery by decorating the surface of polyanhydridenanoparticles with specific carbohydrates to provide “pathogenlike”properties that ensure nanoparticles engage C-type lectinreceptors on DCs. The surface of polyanhydride nanoparticleswas functionalized by covalent linkage of dimannose and lactoseresidues using an amine carboxylic acid coupling reaction.Coculture of functionalized nanoparticles with bone marrow derivedDCs significantly increased cell surface expression ofMHC II, the T cell costimulatory molecules CD86 and CD40,the C-type lectin receptor CIRE and the mannose receptorCD206 over the nonfunctionalized nanoparticles. Both nonfunctionalizedand functionalized nanoparticles were efficientlyinternalized by DCs, indicating that internalization of functionalizednanoparticles was necessary but not sufficient to activateDCs. Blocking the mannose and CIRE receptors prior to theaddition of functionalized nanoparticles to the culture inhibited the increased surface expression of MHC II, CD40 and CD86.Together, these data indicate that engagement of CIRE and the mannose receptor is a key mechanism by which functionalizednanoparticles activate DCs. These studies provide valuable insights into the rational design of targeted nanovaccine platforms toinduce robust immune responses and improve vaccine efficacy