Frank P G, Galbiati F, Volonte D, Razani B, Cohen D E, Marcel Y L, Lisanti M P
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Am J Physiol Cell Physiol. 2001 May;280(5):C1204-14. doi: 10.1152/ajpcell.2001.280.5.C1204.
Caveolin-1 is a principal structural component of caveolae membranes. These membrane microdomains participate in the regulation of signaling, transcytosis, and cholesterol homeostasis at the plasma membrane. In the present study, we determined the effect of caveolin-1 expression on cellular cholesterol efflux mediated by high-density lipoprotein (HDL). We evaluated this effect in parental NIH/3T3 cells as well as in two transformed NIH/3T3 cell lines in which caveolin-1 protein levels are dramatically downregulated. Compared with parental NIH/3T3 cells, these two transformed cell lines effluxed cholesterol more rapidly to HDL. In addition, NIH/3T3 cells harboring caveolin-1 antisense also effluxed cholesterol more rapidly to HDL. However, this effect was not due to changes in total cellular cholesterol content. We further showed that chronic HDL exposure reduced caveolin-1 protein expression in NIH/3T3 cells. HDL exposure also inhibited caveolin-1 promoter activity, suggesting a direct negative effect of HDL on caveolin-1 gene transcription. Moreover, we showed that HDL-induced downregulation of caveolin-1 prevents the uptake of oxidized low-density lipoprotein in human endothelial cells. These data suggest a novel proatherogenic role for caveolin-1, i.e., regarding the uptake and/or transcytosis of modified lipoproteins.
小窝蛋白-1是小窝膜的主要结构成分。这些膜微区参与质膜上信号传导、转胞吞作用和胆固醇稳态的调节。在本研究中，我们确定了小窝蛋白-1表达对高密度脂蛋白（HDL）介导的细胞胆固醇流出的影响。我们在亲代NIH/3T3细胞以及两种小窝蛋白-1蛋白水平显著下调的转化NIH/3T3细胞系中评估了这种影响。与亲代NIH/3T3细胞相比，这两种转化细胞系将胆固醇更快地流出到HDL。此外，携带小窝蛋白-1反义的NIH/3T3细胞也将胆固醇更快地流出到HDL。然而，这种作用并非由于细胞总胆固醇含量的变化。我们进一步表明，慢性HDL暴露降低了NIH/3T3细胞中小窝蛋白-1的蛋白表达。HDL暴露还抑制了小窝蛋白-1启动子活性，表明HDL对小窝蛋白-1基因转录有直接的负向作用。此外，我们表明HDL诱导的小窝蛋白-1下调可阻止人内皮细胞摄取氧化型低密度脂蛋白。这些数据表明小窝蛋白-1具有一种新的促动脉粥样硬化作用，即关于修饰脂蛋白的摄取和/或转胞吞作用。
