Chen W, Silver D L, Smith J D, Tall A R
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
J Biol Chem. 2000 Oct 6;275(40):30794-800. doi: 10.1074/jbc.M004552200.
Scavenger receptor BI (SR-BI) facilitates the efflux of cellular cholesterol to plasma high density lipoprotein (HDL). Recently, the ATP-binding cassette transporter 1 (ABC1) was identified as a key mediator of cholesterol efflux to apolipoproteins and HDL. The goal of the present study was to determine a possible interaction between the SR-BI and ABC1 cholesterol efflux pathways in macrophages. Free cholesterol efflux to HDL was increased ( approximately 2.2-fold) in SR-BI transfected RAW macrophages in association with increased SR-BI protein levels. Treatment of macrophages with 8-bromo-cAMP (cAMP) resulted in a 4.1-fold increase in ABC1 mRNA level and also increased cholesterol efflux to HDL (2.2-fold) and apoA-I (5.5-fold). However, in SR-BI transfected RAW cells, cAMP treatment produced a much smaller increment in cholesterol efflux to HDL (1.1-fold) or apoA-I (3.3-fold) compared with control cells. In macrophages loaded with cholesterol by acetyl-LDL treatment, SR-BI overexpression did not increase cholesterol efflux to HDL but did inhibit cAMP-mediated cholesterol efflux to apoA-I or HDL. SR-BI neutralizing antibody led to a dose- and time-dependent increase of cAMP-mediated cholesterol efflux in both SR-BI transfected and control cells, indicating that SR-BI inhibits ABC1-mediated cholesterol efflux even at low SR-BI expression level. Transfection of a murine ABC1 cDNA into 293 cells led to a 2.3-fold increase of cholesterol efflux to apoA-I, whereas co-transfection of SR-BI with ABC1 blocked this increase in cholesterol efflux. SR-BI and ABC1 appear to have distinct and competing roles in mediating cholesterol flux between HDL and macrophages. In nonpolarized cells, SR-BI promotes the reuptake of cholesterol actively effluxed by ABC1, creating a futile cycle.
清道夫受体BI（SR-BI）促进细胞胆固醇外流至血浆高密度脂蛋白（HDL）。最近，ATP结合盒转运体1（ABC1）被确定为胆固醇外流至载脂蛋白和HDL的关键介质。本研究的目的是确定巨噬细胞中SR-BI和ABC1胆固醇外流途径之间可能的相互作用。在SR-BI转染的RAW巨噬细胞中，游离胆固醇向HDL的外流增加（约2.2倍），同时SR-BI蛋白水平升高。用8-溴-cAMP（cAMP）处理巨噬细胞导致ABC1 mRNA水平增加4.1倍，同时胆固醇向HDL的外流增加（2.2倍），向载脂蛋白A-I的外流增加（5.5倍）。然而，在SR-BI转染的RAW细胞中，与对照细胞相比，cAMP处理使胆固醇向HDL（1.1倍）或载脂蛋白A-I（3.3倍）的外流增加幅度小得多。在用乙酰-LDL处理使巨噬细胞负载胆固醇后，SR-BI的过表达并未增加胆固醇向HDL的外流，但确实抑制了cAMP介导的胆固醇向载脂蛋白A-I或HDL的外流。SR-BI中和抗体导致SR-BI转染细胞和对照细胞中cAMP介导的胆固醇外流呈剂量和时间依赖性增加，表明即使在低SR-BI表达水平下，SR-BI也会抑制ABC1介导的胆固醇外流。将小鼠ABC1 cDNA转染到293细胞中导致胆固醇向载脂蛋白A-I的外流增加2.3倍，而将SR-BI与ABC1共转染则阻断了胆固醇外流的这种增加。SR-BI和ABC1在介导HDL与巨噬细胞之间的胆固醇通量方面似乎具有不同且相互竞争的作用。在非极化细胞中，SR-BI促进由ABC1主动外流的胆固醇的再摄取，从而形成无效循环。
