Liver phospholipid transfer protein (PLTP) expression with a PLTP-null background promotes very low-density lipoprotein production in mice.
Liver phospholipid transfer protein (PLTP) expression with a PLTP-null background promotes very low-density lipoprotein production in mice.
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DOI：
10.1002/hep.25648
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发表时间：
2012-08
期刊：
影响因子：
13.5
通讯作者：
Jiang, Xian-Cheng
中科院分区：
文献类型：
--
作者：
Yazdanyar, Amirfarbod;Jiang, Xian-Cheng
众所周知，血浆磷脂转移蛋白（PLTP）活性影响脂蛋白代谢。肝脏是脂蛋白产生和降解以及 PLTP 表达的主要场所之一。为了解决肝脏表达的 PLTP 对脂蛋白代谢的影响，我们创建了一种小鼠模型，该模型在肝脏中敏锐且特异性地表达 PLTP，且背景为 PLTP 无效。这种小鼠模型制备方法也可普遍用于评估肝脏中许多其他基因的功能。我们发现，与对照组相比，肝脏PLTP表达显着增加血浆非HDL胆固醇（2.7倍，P<0.0001）、非HDL磷脂（2.5倍，P<0.001）和甘油三酯（51%，P<0.01）的水平，但对血浆HDL脂质没有显着影响。 PLTP表达小鼠的血浆apoB水平也显着升高（2.2倍，P<0.001），但apoA-I则没有。为了探索其中的机制，我们检查了新生 VLDL 的脂化和分泌，发现肝脏 PLTP 表达显着增加了肝细胞微粒体腔中的 VLDL 脂化，以及 VLDL 分泌到血浆中。总之，可以制备只在肝脏中表达目的基因而不在其他组织中表达的小鼠模型。我们的研究结果首次表明，肝脏 PLTP 的主要功能是驱动 VLDL 产生，对血浆 PLTP 活性贡献较小，因此对血浆 HDL 水平具有边际影响。
It is known that plasma phospholipid transfer protein (PLTP) activity influences lipoprotein metabolism. The liver is one of the major sites of lipoprotein production and degradation, as well as of PLTP expression. To address the impact of liver-expressed PLTP on lipoprotein metabolism, we created a mouse model that expresses PLTP in the liver acutely and specifically, with a PLTP-null background. This approach in mouse model preparation can also be used universally for evaluating the function of many other genes in the liver. We found that liver PLTP expression dramatically increases plasma levels of non-HDL-cholesterol (2.7-fold, P<0.0001), non-HDL-phospholipid (2.5-fold, P<0.001), and triglyceride (51%, P<0.01), but has no significant influence on plasma HDL-lipids, as compared with controls. Plasma apoB levels were also significantly increased in the PLTP-expressed mice (2.2-fold, P<0.001), but those of apoA-I were not. To explore the mechanism involved, we examined the lipidation and secretion of nascent VLDL, finding that liver PLTP expression significantly increases VLDL lipidation in hepatocyte microsomal lumen, and also VLDL secretion into the plasma. In conclusion, it is possible to prepare a mouse model that expresses the gene of interest only in the liver, but not in other tissues. Our results suggest, for the first time, that the major function of liver PLTP is to drive VLDL production and makes a small contribution to plasma PLTP activity, thus has marginal effect on plasma HDL levels.
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