Lipid rafts on the cell surface are believed to be very important as platforms for various cellular functions. The aim of this study was to know whether defective lipid efflux may influence lipid rafts on the cell surface and their related cellular functions. We investigated macrophages with defective lipid efflux from ATP binding cassette transporter A1-deficient (Abca1-KO) mice. Lipid rafts were evaluated by the following two novel probes: a biotinylated and protease (subtilisin Carlsberg)-nicked derivative of u-toxin and a fluorescein ester of polyethylene glycol-derived cholesterol. Lipid rafts in Abca1-KO macrophages were increased, as demonstrated by both probes. Moreover, activities of nuclear factor kB, mRNA and intracellular distribution, and secretion of tumor necrosis factor-a (TNF-a) were examined after stimulation by lipopolysaccharides (LPSs). LPS-induced responses of the activation of nuclear factor kB and TNF-a were more prompt and accelerated in the Abca1-KO macrophages compared with wild-type macrophages. Modification of lipid rafts by cyclodextrin and nystatin corrected the abnormal response, suggesting an association between the increased lipid rafts and abnormal TNF-a secretion.We report here that Abca1-KO macrophages with defective lipid efflux exhibited increased lipid rafts on the cell surface and accelerated TNF-a secretion. Reverse cholesterol transport (RCT) is one of the major protective systems against atherosclerosis, in which HDL particles play a crucial role as a shuttle carrying cholesterol derived from peripheral tissues to the liver (1). Cholesterol efflux from the cells is the initial step of RCT, in which free apolipoprotein A-I (apoA-I) or small HDLs take up cholesterol from the peripheral cells. We have been trying to elucidate the molecular mechanism for RCT and cholesterol efflux by analyzing the pathophysiology of patients with abnormal HDL metabolism. We have identified molecules involved in cellular cholesterol efflux and apoA-I and HDL binding proteins on macrophages (2-5).Tangier disease (TD) is a model for the impairment of cholesterol efflux from the cells (6, 7). Patients with TD suffer from genetic HDL deficiency, hepatosplenomegaly, orange tonsils, and premature atherosclerosis (8, 9). Many laboratories including ours have reported that mutations in the Abca1 gene lead to defective cholesterol efflux from the cells (10-12). As a result of the mutation(s) in the Abca1 gene, cells from TD patients exhibited a deficiency of apoA-I-mediated cholesterol efflux and a subsequent accumulation of intracellular lipids as lipid droplets, which is closely related to the development of atherosclerosis in this disorder.On the other hand, in the plasma membrane, cholesterol is distributed abundantly in some domain structures Abbreviations: Abca1-KO, ATP binding cassette transporter A1-deficient; apoA-I, apolipoprotein A-I; BCu, biotinylated and protease (subtilisin Carlsberg)-nicked derivative of u-toxin; fPEG-chol, fluorescent polyethylene glycol cholesteryl ether; L...
These findings suggest that ezetimibe improves fasting lipoprotein profiles and postprandial hyperlipidaemia by suppressing intestinal CM production in patients with type IIb hyperlipidaemia and such treatment may prove to be effective in reducing atherosclerosis.
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