Scavenger receptor BI (SR-BIThe levels of plasma high density lipoproteins (HDL) 1 are inversely related to the incidence of atherosclerosis and coronary artery disease (1, 2). The protective effect of HDL is thought to involve the reverse transport of cholesterol from cells in the arterial wall to the liver for disposal (3, 4). The transfer of cholesterol from cells to HDL may result from aqueous diffusion (5, 6) and/or the interaction between a cell surface receptor and HDL (7). A number of HDL-binding proteins have been described (5, 7) but none has been shown to be an authentic HDL receptor mediating cholesterol efflux. Recently a member of the scavenger receptor family, scavenger receptor type B class I (SR-BI), was shown to bind HDL with high affinity and to mediate the selective cellular uptake of HDL cholesteryl ester (CE) (8). SR-BI is highly expressed in steroidogenic tissues and the liver (8 -11), and in vivo evidence suggests that SR-BI expression is under feedback regulation (10). While these results show that SR-BI is an HDL receptor that is likely to provide sterol for steroidogenesis, the exact role of SR-BI in the regulation of HDL metabolism and the maintenance of general cholesterol homeostasis is unknown.In the present study we used SR-BI-transfected cells to evaluate a possible role of SR-BI in HDL-mediated cellular cholesterol efflux. We also sought to establish a relationship between cholesterol efflux and the level of SR-BI expression in a variety of cell types. The results, together with our finding that SR-BI mRNA is expressed in the thickened intima of atheromatous aorta, suggest a potentially important role of SR-BI in the initial steps of cholesterol efflux in the arterial wall.

Background Inflammation is proposed to impair reverse cholesterol transport (RCT), a major atheroprotective function of HDL. This study presents the first integrated functional evidence that inflammation retards numerous components of RCT. Methods and Results We employed sub-acute endotoxemia in the rodent macrophage-to-feces RCT model to assess the effects of inflammation on RCT in vivo, and performed proof of concept experimental endotoxemia studies in humans. Endotoxemia (3mg/kg, SQ) reduced 3H-cholesterol movement from macrophage to plasma and 3H-cholesterol associated with HDL fractions. At 48h bile and fecal counts were markedly reduced consistent with downregulation of hepatic expression of ABCG5, ABCG8 and ABCB11 biliary transporters. Low dose LPS (0.3mg/kg, SQ) also reduced bile and fecal counts, as well as expression of biliary transporters, but in the absence of effects on plasma or liver counts. In vitro, LPS impaired 3H-cholesterol efflux from human macrophages to apoA-I and serum coincident with reduced expression of the cholesterol transporter, ABCA1. During human (3ng/kg; n=20) and murine endotoxemia (3mg/kg, SQ), ex vivo macrophage cholesterol efflux to acute phase HDL was attenuated. Conclusions We provide the first in vivo evidence that inflammation impairs RCT at multiple steps in the RCT pathway, particularly cholesterol flux through liver to bile and feces. Attenuation of RCT and HDL efflux function, independent of HDL-cholesterol levels, may contribute to atherosclerosis in chronic inflammatory states including obesity, metabolic syndrome and type-2 diabetes.

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A cell culture system was employed to test a large number of samples of human serum for the ability to stimulate the efflux of cell cholesterol. The extent of efflux obtained with each specimen was correlated with the serum concentrations of cholesterol, triglycerides, apoprotein (apo) B, apo A-I, apo A-II, and lipoprotein subfractions (ie, high-density lipoprotein 2 [HDL 2 ], HDL 3 , lipoprotein [Lp] A-I, and LpA-I:A-II). In addition, the subsequent esterification of the released cholesterol and the distribution of the synthesized exogenous cholesteryl esters between HDL and low-density lipoprotein/ very-low-density lipoprotein provided estimates of the lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities of each serum. The values for these activities were analyzed for correlations with cell efflux and the various serum parameters. Cell cholesterol efflux best correlated with serum total HDL cholesterol values. HDL 2 and HDL 3 correlated about equally well with efflux, whereas LpA-I demonstrated a much greater association with T he process by which cholesterol in peripheral tissues is transported back to the liver for excretion has been termed reverse cholesterol transport (RCT). While the importance of high-density lipoprotein (HDL) in RCT is now universally accepted, it is not known which specific fractions of HDL are most important. Most in vitro studies have used either native lipoproteins, particularly subclasses of HDL, or reconstituted particles containing apolipoproteins and phospholipids to study cholesterol efflux, which is the first step in RCT. The difficulties in clearly identifying the specific lipoprotein in serum or interstitial fluid that plays the primary role in cholesterol efflux are due to several facts. First, there is a wide variety of particles within the HDL class of lipoproteins, and no single class of particles appears to be uniquely responsible for cholesterol efflux. 1 -2 Second, depending on the method of separation, two subclasses of HDL have been pro- Studies with whole serum have been limited, and it is not known if the quantification of a single serum parameter, or even combinations of parameters, is sufficient to allow the prediction of how individual samples of human serum will influence cellular cholesterol efflux.Cholesterol efflux studies using whole sera are best represented by the investigations of Fielding and colleagues. 68 The initial studies using fibroblasts as the cholesterol donor cell clearly established that sera from individuals differed in their ability to produce changes in net cellular cholesterol efflux. These differences were correlated to a number of clinical conditions that are known to influence serum lipoprotein patterns, such as by guest on May 9, 2018 http://atvb.ahajournals.org/ Downloaded from