Han J, Nicholson A C, Zhou X, Feng J, Gotto A M, Hajjar D P
Center of Vascular Biology, Weill Medical College of Cornell University, New York, New York 10021, USA.
J Biol Chem. 2001 May 11;276(19):16567-72. doi: 10.1074/jbc.M011302200. Epub 2001 Feb 6.
Scavenger receptor class B type I (SR-BI) has recently been identified as a high density lipoprotein (HDL) receptor that mediates bidirectional flux of cholesterol across the plasma membrane. We have previously demonstrated that oxidized low density lipoprotein (OxLDL) will increase expression of another class B scavenger receptor, CD36 (Han, J., Hajjar, D. P., Febbraio, M., and Nicholson, A. C. (1997) J. Biol. Chem. 272, 21654-21659). In studies reported herein, we evaluated the effects of OxLDL on expression of SR-BI in macrophages to determine how exposure to this modified lipoprotein could alter SR-BI expression and cellular lipid flux. OxLDL decreased SR-BI expression in a dose- and time-dependent manner. Incubation with OxLDL had no effect on the membrane distribution of SB-BI, and it decreased expression of both cytosolic and membrane protein. Consistent with its effect on SR-BI protein expression, OxLDL decreased SR-BI mRNA in a dose-dependent manner. The ability of OxLDL to decrease SR-BI expression was dependent on the degree of LDL oxidation. OxLDL decreased both [(14)C]cholesteryl oleate/HDL uptake and efflux of [(14)C]cholesterol to HDL in a time-dependent manner. Incubation of macrophages with 7-ketocholesterol, but not free cholesterol, also inhibited expression of SR-BI. Finally, we demonstrate that the effect of OxLDL on SR-BI is dependent on the differentiation state of the monocyte/macrophage. These results imply that in addition to its effect in inducing foam cell formation in macrophages through increased uptake of oxidized lipids, OxLDL may also enhance foam cell formation by altering SR-BI-mediated lipid flux across the cell membrane.
I型B类清道夫受体（SR-BI）最近被确定为一种高密度脂蛋白（HDL）受体，可介导胆固醇跨质膜的双向流动。我们之前已经证明，氧化型低密度脂蛋白（OxLDL）会增加另一类B类清道夫受体CD36的表达（Han, J., Hajjar, D. P., Febbraio, M., and Nicholson, A. C. (1997) J. Biol. Chem. 272, 21654 - 21659）。在本文报道的研究中，我们评估了OxLDL对巨噬细胞中SR-BI表达的影响，以确定暴露于这种修饰的脂蛋白如何改变SR-BI表达和细胞脂质流动。OxLDL以剂量和时间依赖性方式降低SR-BI表达。与OxLDL孵育对SB-BI的膜分布没有影响，并且它降低了胞质和膜蛋白的表达。与其对SR-BI蛋白表达的影响一致，OxLDL以剂量依赖性方式降低SR-BI mRNA。OxLDL降低SR-BI表达的能力取决于LDL氧化的程度。OxLDL以时间依赖性方式降低[(14)C]胆固醇油酸酯/HDL摄取以及[(14)C]胆固醇向HDL的流出。用7-酮胆固醇而非游离胆固醇孵育巨噬细胞也抑制了SR-BI的表达。最后，我们证明OxLDL对SR-BI的影响取决于单核细胞/巨噬细胞的分化状态。这些结果表明，除了通过增加氧化脂质摄取在巨噬细胞中诱导泡沫细胞形成的作用外，OxLDL还可能通过改变SR-BI介导的跨细胞膜脂质流动来增强泡沫细胞形成。
