Phospholipid Transfer Protein Is Expressed in Cerebrovascular Endothelial Cells and Involved in High Density Lipoprotein Biogenesis and Remodeling at the Blood- Brain Barrier*
Phospholipid Transfer Protein Is Expressed in Cerebrovascular Endothelial Cells and Involved in High Density Lipoprotein Biogenesis and Remodeling at the Blood- Brain Barrier*
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DOI：
10.1074/jbc.m113.499129
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发表时间：
2014-02-21
影响因子：
4.8
通讯作者：
Panzenboeck, Ute
中科院分区：
文献类型：
--
作者：
Manavalan, Anil Paul Chirackal;Kober, Alexandra;Panzenboeck, Ute
背景：肝X受体激活促进血脑屏障（BBB）处高密度脂蛋白样颗粒的形成。结果：脑血管内皮细胞表达磷脂转移蛋白（PLTP），传递磷脂，重塑HDL，支持细胞胆固醇外排。结论：PLTP参与了血脑屏障内HDL的生成和重塑。意义：我们证明了PLTP在血脑界面HDL代谢中的直接作用。磷脂转移蛋白（PLTP）是参与血浆高密度脂蛋白（HDL）生物发生和重塑的关键蛋白。HDL具有多种神经保护特性。我们之前报道过，在猪脑毛细血管内皮细胞（pBCEC）组成的血脑屏障（BBB）体外模型中，肝脏X受体（LXR）的激活促进细胞胆固醇外溢和高密度脂蛋白样颗粒的形成。在这里，我们报道了PLTP的合成、调控及其在血脑屏障中高密度脂蛋白代谢中的关键作用。我们发现pcec高表达和分泌PLTP。在模拟血脑屏障的极化体外模型中，pBCEC优先向基底外侧（脑实质）室分泌磷脂转移活性PLTP。24(S)-羟基胆固醇（一种脑胆固醇代谢物）或TO901317（一种合成的LXR激动剂）激活LXR后，PLTP表达水平和磷脂转移活性增强（高达2.5倍）。TO901317可提高C57/BL6小鼠BCEC中PLTP活性。将HDL3与人血浆源性活性PLTP进行预孵育，可形成更大和更小的HDL颗粒，并可将生成的HDL颗粒从pBCEC中去除胆固醇的能力提高3倍。通过二维交叉免疫电泳检测，pbcec衍生的上清液中HDL3生成了Pre- HDL， LXR激活后，Pre- HDL的生成明显增加（1.9倍）。此外，RNA干扰介导的PLTP沉默（高达75%）减少了pcec中apoa - i依赖性（67%）和hdl3依赖性（30%）的胆固醇外排。基于这些发现，我们提出PLTP积极参与血脑屏障的脂质转移、胆固醇外排、HDL生成和重塑。
Background: Liver X receptor activation promotes formation of HDL-like particles at the blood-brain barrier (BBB). Results: Cerebrovascular endothelial cells express phospholipid transfer protein (PLTP) that transfers phospholipids, remodels HDL, and supports cellular cholesterol efflux. Conclusion: PLTP is involved in HDL genesis and remodeling at the BBB. Significance: We demonstrate a direct role of PLTP in HDL metabolism at the blood-brain interface.Phospholipid transfer protein (PLTP) is a key protein involved in biogenesis and remodeling of plasma HDL. Several neuroprotective properties have been ascribed to HDL. We reported earlier that liver X receptor (LXR) activation promotes cellular cholesterol efflux and formation of HDL-like particles in an established in vitro model of the blood-brain barrier (BBB) consisting of primary porcine brain capillary endothelial cells (pBCEC). Here, we report PLTP synthesis, regulation, and its key role in HDL metabolism at the BBB. We demonstrate that PLTP is highly expressed and secreted by pBCEC. In a polarized in vitro model mimicking the BBB, pBCEC secreted phospholipid-transfer active PLTP preferentially to the basolateral (brain parenchymal) compartment. PLTP expression levels and phospholipid transfer activity were enhanced (up to 2.5-fold) by LXR activation using 24(S)-hydroxycholesterol (a cerebral cholesterol metabolite) or TO901317 (a synthetic LXR agonist). TO901317 administration elevated PLTP activity in BCEC from C57/BL6 mice. Preincubation of HDL3 with human plasma-derived active PLTP resulted in the formation of smaller and larger HDL particles and enhanced the capacity of the generated HDL particles to remove cholesterol from pBCEC by up to 3-fold. Pre--HDL, detected by two-dimensional crossed immunoelectrophoresis, was generated from HDL3 in pBCEC-derived supernatants, and their generation was markedly enhanced (1.9-fold) upon LXR activation. Furthermore, RNA interference-mediated PLTP silencing (up to 75%) reduced both apoA-I-dependent (67%) and HDL3-dependent (30%) cholesterol efflux from pBCEC. Based on these findings, we propose that PLTP is actively involved in lipid transfer, cholesterol efflux, HDL genesis, and remodeling at the BBB.