Lie Jessica, de Crom Rini, van Gent Teus, van Haperen Rien, Scheek Leo, Sadeghi-Niaraki Farah, van Tol Arie
Departments of Biochemistry, Erasmus University Medical Center, P O Box 1738, 3000 DR Rotterdam, The Netherlands.
J Lipid Res. 2004 May;45(5):805-11. doi: 10.1194/jlr.M300487-JLR200. Epub 2004 Mar 1.
Plasma phospholipid transfer protein (PLTP) transfers phospholipids between lipoproteins and mediates HDL conversion. PLTP-overexpressing mice have increased atherosclerosis. However, mice do not express cholesteryl ester transfer protein (CETP), which is involved in the same metabolic pathways as PLTP. Therefore, we studied atherosclerosis in heterozygous LDL receptor-deficient (LDLR(+/-)) mice expressing both human CETP and human PLTP. We used two transgenic lines with moderately and highly elevated plasma PLTP activity. In LDLR(+/-)/huCETPtg mice, cholesterol is present in both LDL and HDL. Both are decreased in LDLR(+/-)/huCETPtg/huPLTPtg mice (>50%). An atherogenic diet resulted in high levels of VLDL+LDL cholesterol. PLTP expression caused a strong PLTP dose-dependent decrease in VLDL and LDL cholesterol (-26% and -69%) and a decrease in HDL cholesterol (-70%). Surprisingly, atherosclerosis was increased in the two transgenic lines with moderately and highly elevated plasma PLTP activity (1.9-fold and 4.4-fold, respectively), indicating that the adverse effect of the reduction in plasma HDL outweighs the beneficial effect of the reduction in apolipoprotein B (apoB)-containing lipoproteins. The activities of the antiatherogenic enzymes paraoxonase and platelet-activating factor acetyl hydrolase were both PLTP dose-dependently reduced ( approximately -33% and -65%, respectively). We conclude that expression of PLTP in this animal model results in increased atherosclerosis in spite of reduced apoB-containing lipoproteins, by reduction of HDL and of HDL-associated antioxidant enzyme activities.
血浆磷脂转运蛋白（PLTP）在脂蛋白之间转运磷脂并介导高密度脂蛋白（HDL）的转化。过度表达PLTP的小鼠动脉粥样硬化加剧。然而，小鼠不表达胆固醇酯转运蛋白（CETP），而CETP与PLTP参与相同的代谢途径。因此，我们研究了同时表达人CETP和人PLTP的杂合低密度脂蛋白受体缺陷（LDLR(+/-)）小鼠的动脉粥样硬化情况。我们使用了两个血浆PLTP活性中度和高度升高的转基因品系。在LDLR(+/-)/huCETPtg小鼠中，胆固醇同时存在于低密度脂蛋白（LDL）和HDL中。在LDLR(+/-)/huCETPtg/huPLTPtg小鼠中，两者均减少（>50%）。致动脉粥样化饮食导致极低密度脂蛋白（VLDL）+LDL胆固醇水平升高。PLTP表达导致VLDL和LDL胆固醇呈强烈的PLTP剂量依赖性降低（分别为-26%和-69%）以及HDL胆固醇降低（-70%）。令人惊讶的是，血浆PLTP活性中度和高度升高的两个转基因品系中的动脉粥样硬化加剧（分别为1.9倍和4.4倍），这表明血浆HDL降低的不利影响超过了含载脂蛋白B（apoB）的脂蛋白降低的有益影响。抗动脉粥样硬化酶对氧磷酶和血小板活化因子乙酰水解酶的活性均呈PLTP剂量依赖性降低（分别约为-33%和-65%）。我们得出结论，在该动物模型中，尽管含apoB的脂蛋白减少，但PLTP的表达通过降低HDL以及与HDL相关的抗氧化酶活性，导致动脉粥样硬化加剧。
