Aims. Diabetes is associated with atherogenesis and macrophage-foam cell formation, due in part to a decrease in HDL-mediated cholesterol efflux from macrophages. This Study examined the expression of proteins involved in cholesterol transport, I e ABCA1 and SR-BI, under diabetic conditions Methods and results. ABCA1 expression was similar, whereas SR-BI expression (mRNA and protein) was significantly increased in mouse peritoneal macrophages (MPM) harvested from C57BI/6 diabetic mice, compared to MPM from control non-diabetic mice similar results were obtained in vitro in J-774A I macrophage-like cell line Incubated with high (30 mM) vs low (5 mM) glucose concentrations Accordingly, association and internalization of HDL to MPM from diabetic mice, or to J-774A I macrophages grown Under diabetic conditions was significantly higher compared to control cells Unexpectedly, however, increased macrophage SR-BI expression was associated With a Substantial reduction in HDL-mediated cholesterol efflux from the macrophages Moreover, total cellular cholesterol content was increased by 28% in macrophages incubated with HDL under high glucose concentrations, compared to low glucose concentrations This effect was abolished by a rabbit polyclonal anti-SR-BI, which blocks binding to the receptor, or alternatively by using BLT1, a specific inhibitor of lipid transport via the SR-BI Conclusions Diabetes stimulates the expression of SR-BI in macrophages and leads to a shift in its activity from HDL-mediated cholesterol efflux to HDL-mediated cholesterol Influx These effects may lead to Increased foam cell formation and atherosclerosis development. (C) 2009 Elsevier Inc. All rights reserved