Jiang X, Francone O L, Bruce C, Milne R, Mar J, Walsh A, Breslow J L, Tall A R
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA.
J Clin Invest. 1996 Nov 15;98(10):2373-80. doi: 10.1172/JCI119050.
Human plasma phospholipid transfer protein (PLTP) circulates bound to high density lipoprotein (HDL) and mediates both net transfer and exchange of phospholipids between different lipoproteins. However, its overall function in lipoprotein metabolism is unknown. To assess the effects of increased plasma levels of PLTP, human PLTP transgenic mice were established using the human PLTP gene driven by its natural promoter. One line of PLTP transgenic mice with moderate expression of PLTP mRNA and protein was obtained. The order of human PLTP mRNA expression in tissues was: liver, kidney, brain, small intestine > lung > spleen > heart, adipose tissue. Western blotting using a human PLTP monoclonal antibody revealed authentic human PLTP (Mr 80 kD) in plasma. Plasma PLTP activity was increased by 29% in PLTP transgenic mice. However, plasma lipoprotein analysis, comparing PLTP transgenic mice to control littermates, revealed no significant changes in the plasma lipoprotein lipids or apolipoproteins. Since previous studies have shown that human cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase only function optimally in human apoAI transgenic mice, the human PLTP transgenic mice were cross-bred with human apoAI transgenic mice. In the human apoAI transgenic background, PLTP expression resulted in increased PLTP activity (47%), HDL phospholipid (26%), cholesteryl ester (24%), free cholesterol (37%), and apoAI (22%). There was a major increase of apoAI in prebeta-HDL (56%) and a small increase in alpha-HDL (14%). The size distribution of HDL particles within alpha- and prebeta-migrating species was not changed. The results suggest that PLTP increases the influx of phospholipid and secondarily cholesterol into HDL, leading to an increase in potentially antiatherogenic prebeta-HDL particles.
人血浆磷脂转运蛋白（PLTP）与高密度脂蛋白（HDL）结合循环，并介导不同脂蛋白之间磷脂的净转运和交换。然而，其在脂蛋白代谢中的整体功能尚不清楚。为了评估血浆中PLTP水平升高的影响，利用由其天然启动子驱动的人PLTP基因建立了人PLTP转基因小鼠。获得了一组PLTP mRNA和蛋白表达适度的PLTP转基因小鼠。人PLTP mRNA在组织中的表达顺序为：肝脏、肾脏、大脑、小肠＞肺＞脾脏＞心脏、脂肪组织。使用人PLTP单克隆抗体进行的蛋白质印迹分析显示血浆中存在真实的人PLTP（分子量80 kD）。PLTP转基因小鼠的血浆PLTP活性增加了29%。然而，将PLTP转基因小鼠与对照同窝小鼠进行比较的血浆脂蛋白分析显示，血浆脂蛋白脂质或载脂蛋白没有显著变化。由于先前的研究表明人胆固醇酯转运蛋白和卵磷脂：胆固醇酰基转移酶仅在人载脂蛋白AI转基因小鼠中发挥最佳功能，因此将人PLTP转基因小鼠与载脂蛋白AI转基因小鼠进行杂交。在人载脂蛋白AI转基因背景下，PLTP表达导致PLTP活性增加（47%）、HDL磷脂增加（26%）、胆固醇酯增加（24%）、游离胆固醇增加（37%）和载脂蛋白AI增加（22%）。前β-HDL中的载脂蛋白AI大幅增加（56%），α-HDL略有增加（14%）。α-和前β-迁移物种内HDL颗粒的大小分布没有改变。结果表明，PLTP增加了磷脂和继发胆固醇向HDL的流入，导致潜在抗动脉粥样硬化的前β-HDL颗粒增加。
