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Rationale: Association of habitual coffee consumption with coronary heart disease morbidity and mortality has not been established. We hypothesized that coffee may enhance reverse cholesterol transport (RCT) as the antiatherogenic properties of high-density lipoprotein (HDL). Objective: This study was to investigate whether the phenolic acids of coffee and coffee regulates RCT from macrophages in vitro, ex vivo and in vivo. Methods and Results: Caffeic acid and ferulic acid, the major phenolic acids of coffee, enhanced cholesterol efflux from THP-1 macrophages mediated by HDL, but not apoA-I. Furthermore, these phenolic acids increased both the mRNA and protein levels of ATP-binding cassette transporter (ABC)G1 and scavenger receptor class B type I (SR-BI), but not ABCA1. Eight healthy volunteers were recruited for the ex vivo study, and blood samples were taken before and 30 minutes after consumption of coffee or water in a crossover study. The mRNA as well as protein levels of ABCG1, SR-BI, and cholesterol efflux by HDL were increased in the macrophages differentiated under autologous sera obtained after coffee consumption compared to baseline sera. Finally, effects of coffee and phenolic acid on in vivo RCT were assessed by intraperitoneally injecting Key Words: HDL cholesterol Ⅲ efflux Ⅲ coffee Ⅲ phenolic acid H igh-density lipoproteins (HDLs) have been shown to be inversely associated with the risk of atherosclerotic cardiovascular disease (CVD) 1,2 and thus considered as antiatherogenic lipoproteins. Among antiatherogenic mechanisms including beneficial effects on inflammation, impaired endothelial function or hypercoagulation, HDL exerts the antiatherogenic property primarily by facilitating the efflux of cholesterol from peripheral tissues and transport it back to the liver in a process called reverse cholesterol transport (RCT). A major breakthrough in the understanding of the mechanism of RCT came with the discovery of the ATP binding cassette transporter (ABC)A1. Lipid-poor apolipoprotein (apo)A-I contributes to ABCA1-mediated cholesterol efflux from cells, but not HDL. 3,4 Another ABC transporter, ABCG1, is also involved in the cholesterol efflux from macrophages mediated by HDL, but not apoA-I. 4,5 Scavenger receptor class B type I (SR-BI) is also known to promote HDL-mediated cellular cholesterol efflux. 6 Furthermore, the pivotal roles of these molecules on intracellular cholesterol homeostasis, associated with reverse cholesterol transport, have also been confirmed by animal studies where deletions of ABCA1, 7 ABCG1, 8 and SR-BI 9 in macrophages accelerated the development of atherosclerosis.Coffee is among the most widely consumed beverages worldwide. The relationship between coffee consumption and the incidence of CVD has been studied extensively. 10 -12 In addition, a recent study reported that regular coffee consumption might be associated with a decreased cardiovascular mortality rate. 13 Coffee beans are known to be abundant in antioxidant phenolic acids, chlorogenic acid. Indeed, Xia M et...

Objective-ATP-binding cassette transporter A1 (ABCA1) and ABCG1 are key molecules in an initial step of reverse cholesterol transport (RCT), a major antiatherogenic property of high-density lipoprotein (HDL). The ubiquitinproteasome system (UPS) mediates nonlysosomal pathways for protein degradation and is known to be involved in atherosclerosis. However, little is known about the effects of the UPS on these molecules and overall RCT. We therefore investigated whether UPS inhibition affects ABCA1/G1 expression in macrophages and RCT in vitro and in vivo. Methods and Results-Various proteasome inhibitors increased ABCA1/G1 expression in macrophages, translating into enhanced apolipoprotein A-I-and HDL-mediated cholesterol efflux from macrophages. ABCA1 and ABCG1 were found to undergo polyubiquitination in the macrophages and HEK293 cells overexpressing these proteins, and pulse-chase analysis revealed that proteasome inhibitors inhibited ABCA1/G1 protein degradation. In in vivo experiments, the proteasome inhibitor bortezomib increased ABCA1/G1 protein levels in mouse peritoneal macrophages, and RCT assays showed that it significantly increased the fecal (54% increase compared with saline) and plasma (23%) appearances of the tracer derived from intraperitoneally injected 3 H-cholesterol-labeled macrophages. Conclusion-The present study provided evidence that the UPS is involved in ABCA1/G1 degradation, thereby affecting RCT in vivo. Therefore, specific inhibition of the UPS pathway might lead to a novel HDL therapy that enhances RCT. Key Words: ABC Transporter Ⅲ Macrophages Ⅲ HDL Ⅲ reverse cholesterol transport Ⅲ ubiquitin-proteasome system H igh-density lipoprotein (HDL) removes cholesterol pathologically accumulated in atherosclerotic lesion macrophages and transports it back to the liver for subsequent conversion to bile in a process called reverse cholesterol transport (RCT). 1,2 ATP-binding cassette transporter A1 (ABCA1) and ABCG1 play essential roles in cholesterol efflux from macrophages and HDL formation by acting in a sequential manner: ABCA1 generates nascent HDL particles from lipid-poor apolipoprotein A-I (apoA-I), 3 which then facilitate cholesterol efflux via ABCG1, followed by formation of mature HDL particles. 4 Deletion of both ABCA1 and ABCG1 in macrophages reportedly accelerated atherosclerotic legion development as compared with deletion of either ABCA1 or ABCG1, 5 indicating that ABCA1 and ABCG1 have a synergetic role in antiatherogenesis. See accompanying article on page 1939Evidence regarding the regulation of ABCA1/G1 expression, such as via transactivation by ligand-activated liver X receptor/retinoid X receptor heterodimer, 6 has been accumulating. ABCA1 and ABCG1 have been emerging as therapeutic targets for the treatment of atherosclerotic diseases because enhancement of their expression can promote RCT by increasing cholesterol efflux from macrophages and raising HDL levels. However, strategies using liver X receptor ligands suffer from major drawbacks, including development of fat...