Cholesterol efflux occurs by different pathways, including transport mediated by specific proteins. We determined the effect of enriching cells with free cholesterol (FC) on the release of FC to human serum. Loading Fu5AH cells with FC had no effect on fractional efflux, whereas enriching mouse peritoneal macrophages (MPMs) resulted in a doubling of fractional efflux. Efflux from cholesterolnormal MPM and Fu5AH cells to 15 human sera correlated well with HDL parameters. However, these relationships were reduced or lost with cholesterol-loaded MPMs. Using macrophages from scavenger receptor class B type I (SR-BI)-, ABCA1-, and ABCG1-knockout mice, together with inhibitors of SR-BI-and ABCA1-mediated efflux, we were able to quantitate efflux upon loading macrophages with excess cholesterol and to establish the contributions of the various efflux pathways in cholesterol-normal and -enriched cells. The removal of ABCA1 had essentially no effect on the total efflux when cell cholesterol levels were normal. However, in cholesterol-enriched cells, the removal of ABCA1 reduced efflux by 50%. Approximately 20% of the efflux stimulated by FC-loading MPM is attributable to ABCG1. The SR-BI contribution to efflux was small. Another pathway that is present in all cells is aqueous diffusion. Our studies demonstrate that this mechanism is one of the major contributors to efflux, particularly in cholesterol-normal cells.-

CEC is impaired in RA and SLE, with a specific mechanism pattern in each disease not depending on serum HDL levels. These findings provide a new mechanism for the increased atherosclerotic risk in RA and SLE patients.

Several studies have demonstrated that polyphenol-enriched diets may have beneficial effects against the development of degenerative diseases, including atherosclerosis and disorders affecting the central nervous system. This activity has been associated not only with antioxidant and anti-inflammatory properties, but also with additional mechanisms, such as the modulation of lipid metabolism and gut microbiota function. However, long-term studies on humans provided controversial results, making the prediction of polyphenol impact on health uncertain. The aim of this review is to provide an overview and critical analysis of the literature related to the effects of the principal dietary polyphenols on cardiovascular and neurodegenerative disorders. We critically considered and meta-analyzed randomized controlled clinical trials involving subjects taking polyphenol-based supplements. Although some polyphenols might improve specific markers of cardiovascular risk and cognitive status, many inconsistent data are present in literature. Therefore, definitive recommendations for the use of these compounds in the prevention of cardiovascular disease and cognitive decline are currently not applicable. Once pivotal aspects for the definition of polyphenol bioactivity, such as the characterization of pharmacokinetics and safety, are addressed, it will be possible to have a clear picture of the realistic potential of polyphenols for disease prevention.

Objective-ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of lipids from cells to lipid-poor apolipoproteins. In this article, we characterize the effect of probucol on cellular ABCA1-mediated lipid efflux. Methods and Results-Probucol inhibited cholesterol efflux up to 80% in J774 macrophages expressing ABCA1. In Fu5AH hepatoma cells that contain scavenger receptor class B, type I, but not functional ABCA1, we observed no effect of probucol on cholesterol efflux. Probucol inhibited cholesterol efflux from normal human skin fibroblasts but not from fibroblasts from a Tangier patient. Fluorescent confocal microscopy and biotinylation assay demonstrated that in J774 cells probucol impaired the translocation of ABCA1 from intracellular compartments to the plasma membrane. Probucol also inhibited the formation of an ABCA1-linked cholesterol oxidase sensitive plasma membrane domain. Consistent with the inhibitory effect on ABCA1 translocation to the plasma membrane, probucol reduced cell surface-specific Key Words: probucol Ⅲ lipid efflux Ⅲ ABCA1 Ⅲ macrophages Ⅲ fibroblasts P robucol is a lipid-lowering drug that has been extensively investigated since its introduction in the early 1970s. 1 Among its most dramatic effects is the ability to promote the regression of cutaneous and tendinous xanthoma, and this effect appears to be independent of its cholesterol-lowering effect. 1,2 However, probucol also significantly reduces plasma high-density lipoproteins (HDLs). These facts have made this drug very controversial. It has been reported that probucol treatment induced a more rapid progression of atherosclerotic lesions 3 in apolipoprotein E (apoE) knockout mice. In contrast, a recent study demonstrated that probucol treatment of scavenger receptor class B type I (SR-BI)/apoE double knockout mice prevents the dramatic early coronary heart disease and death that is a characteristic of these animals. 4 Just as the data on probucol effects in vivo are contradictory, so too are the results from a number of experiments that have been conducted to study the action of probucol on cholesterol metabolism in vitro. Yamamoto et al 5 measured the effect of probucol on the change in cholesterol mass on incubation of THP-1 macrophages with HDLs and observed a significant reduction consistent with a probucol-mediated increase in the net efflux of cholesterol. A similar result was obtained by Goldberg and Mendez 6 using human skin fibroblasts. In contrast, a subsequent investigation failed to observe any probucol stimulation in the efflux of cholesterol from a number of cell types. 7 It has been demonstrated that specific cell surface proteins play an important role in mediating the flux of cholesterol between cells and extracellular acceptors (for a review see Yancey et al 8 ). SR-BI facilitates the selective uptake of HDL cholesteryl ester (CE) and enhances the bidirectional flux of free cholesterol (FC) between cells and HDLs. 9 ATP-binding cassette AI (ABCA1) has been shown to bind lipid-free or lipid-poor apoprotei...

Abstract-To test the hypothesis that apolipoprotein A-I (apoA-I) functions specifically to inhibit atherosclerosis independent of the level of high-density lipoprotein cholesterol (HDL-C) by promoting both reverse cholesterol transport and HDL antiinflammatory function in vivo, we established a murine atherosclerosis model of apoA-I deficiency in which the level of HDL-C is well maintained. ApoA-I Ϫ/Ϫ mice were crossed with atherosclerosis susceptible low-density lipoprotein receptor Ϫ/Ϫ /apobec Ϫ/Ϫ (LA) mice to generate LA mice with apoA