Rinninger F, Wang N, Ramakrishnan R, Jiang X C, Tall A R
College of Physicians and Surgeons of Columbia University, Department of Medicine, Division of Molecular Medicine, New York, NY 10032, USA.
Arterioscler Thromb Vasc Biol. 1999 May;19(5):1325-32. doi: 10.1161/01.atv.19.5.1325.
Recently, the class B, type I scavenger receptor (SR-BI) has been shown to mediate the selective uptake of high density lipoprotein (HDL) cholesteryl esters (CEs), ie, lipid uptake independent of HDL holoparticle uptake. In vivo, this selective uptake delivers CEs to the liver for excretion and to steroidogenic tissues for hormone synthesis. Probucol, a hydrophobic antioxidant drug, lowers plasma cholesterol in humans and rodents and may inhibit progression of atherosclerosis and postangioplasty restenosis. In this study, the effect of probucol on HDL selective CE uptake was investigated in mice and in cells expressing SR-BI. Probucol feeding lowered plasma HDL cholesterol and markedly increased selective CE uptake from HDL in the liver and adrenal glands. However, probucol did not alter SR-BI protein levels in membranes from these organs. When incubated with control Chinese hamster ovary (CHO) cells, HDL isolated from probucol-treated mice (P-HDL) and HDL from control mice (C-HDL) showed similar low selective uptake of CEs. However, when incubated with SR-BI-transfected CHO cells, P-HDL showed a 2-fold increase in selective uptake compared with C-HDL. In an adrenal cell line (Y1-BS1), which expresses SR-BI in an adrenocorticotropic hormone-inducible manner, P-HDL showed significantly greater selective CE uptake than did C-HDL, and the differential response was amplified by adrenocorticotropic hormone treatment. In contrast to P-HDL, incorporation of this compound into HDL in vitro did not result in stimulation of selective CE uptake by SR-BI-transfected CHO cells, even though a significant mass of probucol could be detected in the HDL preparation. The specific interaction of P-HDL with SR-BI in cell culture could be observed after only 24 hours of probucol feeding, when there were minimal changes in HDL size and composition. Thus, probucol or one of its metabolites increases selective CE uptake in vivo by modifying HDL in a way that causes enhanced interaction with SR-BI. The increased interaction of P-HDL with SR-BI in the liver and arterial wall may be partly responsible for the effects of probucol on atherosclerosis and restenosis.
最近研究表明，B类I型清道夫受体（SR-BI）可介导高密度脂蛋白（HDL）胆固醇酯（CE）的选择性摄取，即脂质摄取独立于HDL全颗粒摄取。在体内，这种选择性摄取将CE转运至肝脏进行排泄，并转运至类固醇生成组织用于激素合成。普罗布考是一种疏水抗氧化药物，可降低人和啮齿动物的血浆胆固醇，可能抑制动脉粥样硬化进展和血管成形术后再狭窄。在本研究中，研究了普罗布考对小鼠及表达SR-BI的细胞中HDL选择性CE摄取的影响。给予普罗布考可降低血浆HDL胆固醇，并显著增加肝脏和肾上腺中HDL的选择性CE摄取。然而，普罗布考并未改变这些器官膜中SR-BI蛋白水平。当与对照中国仓鼠卵巢（CHO）细胞孵育时，从普罗布考处理的小鼠中分离的HDL（P-HDL）和对照小鼠的HDL（C-HDL）显示出相似的低CE选择性摄取。然而，当与SR-BI转染的CHO细胞孵育时，与C-HDL相比，P-HDL的选择性摄取增加了2倍。在肾上腺细胞系（Y1-BS1）中，SR-BI以促肾上腺皮质激素诱导的方式表达，P-HDL显示出比C-HDL显著更高的选择性CE摄取，促肾上腺皮质激素处理可放大这种差异反应。与P-HDL相反，即使在HDL制剂中可检测到大量普罗布考，在体外将该化合物掺入HDL中也不会导致SR-BI转染的CHO细胞对CE的选择性摄取增加。仅在给予普罗布考24小时后，当HDL大小和组成变化最小时，即可在细胞培养中观察到P-HDL与SR-BI的特异性相互作用。因此，普罗布考或其代谢产物之一通过以增强与SR-BI相互作用的方式修饰HDL，从而增加体内CE的选择性摄取。P-HDL与肝脏和动脉壁中SR-BI相互作用的增加可能部分解释了普罗布考对动脉粥样硬化和再狭窄的作用。
