Moerland Matthijs, Anghelescu Nora, Samyn Hannelore, van Haperen Rien, van Gent Teus, Strouboulis John, van Tol Arie, Grosveld Frank, de Crom Rini
Department of Cell Biology and Genetics, Erasmus University Medical Center, 3000 CA, Rotterdam, The Netherlands.
Transgenic Res. 2007 Aug;16(4):503-13. doi: 10.1007/s11248-007-9094-y. Epub 2007 Apr 17.
One main determinant in high-density lipoprotein (HDL) metabolism is phospholipid transfer protein (PLTP), a plasma protein that is associated with HDL. In transgenic mice overexpressing human PLTP we found that elevated plasma PLTP levels dose-dependently increased the susceptibility to diet-induced atherosclerosis. This could be mainly due to the fact that most functions of PLTP are potentially atherogenic, such as decreasing plasma HDL levels. To further elucidate the role of PLTP in lipoprotein metabolism and atherosclerosis we generated a novel transgenic mouse model that allows conditional expression of human PLTP. In this mouse model a human PLTP encoding sequence is controlled by a Tet-On system. Upon induction of PLTP expression, our mouse model showed a strongly increased PLTP activity (from 3.0 +/- 0.6 to 11.4 +/- 2.8 AU, p < 0.001). The increase in PLTP activity resulted in an acute decrease in plasma cholesterol of 33% and a comparable decrease in phospholipids. The decrease in total plasma cholesterol and phospholipids was caused by a 35% decrease in HDL-cholesterol level and a 41% decrease in HDL-phospholipid level. These results demonstrate the feasibility of our mouse model to induce an acute elevation of PLTP activity, which is easily reversible. As a direct consequence of an increase in PLTP activity, HDL-cholesterol and HDL-phospholipid levels strongly decrease. Using this mouse model, it will be possible to study the effects of acute elevation of PLTP activity on lipoprotein metabolism and pre-existing atherosclerosis.
高密度脂蛋白（HDL）代谢的一个主要决定因素是磷脂转运蛋白（PLTP），它是一种与HDL相关的血浆蛋白。在过表达人PLTP的转基因小鼠中，我们发现血浆PLTP水平升高会剂量依赖性地增加饮食诱导的动脉粥样硬化易感性。这主要可能是由于PLTP的大多数功能都具有潜在的致动脉粥样硬化作用，比如降低血浆HDL水平。为了进一步阐明PLTP在脂蛋白代谢和动脉粥样硬化中的作用，我们构建了一种新型转基因小鼠模型，该模型允许人PLTP的条件性表达。在这个小鼠模型中，人PLTP编码序列由Tet-On系统控制。诱导PLTP表达后，我们的小鼠模型显示PLTP活性大幅增加（从3.0±0.6 AU增加到11.4±2.8 AU，p<0.001）。PLTP活性的增加导致血浆胆固醇急性降低33%，磷脂也有类似程度的降低。血浆总胆固醇和磷脂的降低是由HDL胆固醇水平降低35%和HDL磷脂水平降低41%引起的。这些结果证明了我们的小鼠模型诱导PLTP活性急性升高的可行性，而且这种升高很容易逆转。作为PLTP活性增加的直接结果，HDL胆固醇和HDL磷脂水平大幅降低。利用这个小鼠模型，将有可能研究PLTP活性急性升高对脂蛋白代谢和已存在的动脉粥样硬化的影响。
