Apolipoprotein C-III and the metabolic basis for hypertriglyceridemia and the dense low-density lipoprotein phenotype.
Apolipoprotein C-III and the metabolic basis for hypertriglyceridemia and the dense low-density lipoprotein phenotype.
复制标题
载脂蛋白C-III和高甘油三酸酯血症和致密的低密度脂蛋白表型的代谢基。
DOI：
10.1161/circulationaha.109.875807
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发表时间：
2010-04-20
期刊：
影响因子：
37.8
通讯作者：
Sacks FM
中科院分区：
文献类型：
--
作者：
Zheng C;Khoo C;Furtado J;Sacks FM
在这里，我们的目标是确定高甘油三酯血症的载脂蛋白B脂蛋白代谢缺陷，重点是载脂蛋白C-III和载脂蛋白E。我们用抗apoC-III和抗apoE免疫亲和层析和超速离心法研究了9例中度高甘油三酯血症患者和12例正常对照组血浆apoB的21个不同亚组分的转运。高甘油三酯血症的特征是肝脏分泌的极低密度脂蛋白(VLDL)增加了3倍，其中有apoC-III但没有apoE的VLDL的分泌减少了50%，同时有apoC-III和apoE的VLDL的分泌减少了50%(P均<0.05)。这种极低密度脂蛋白分泌模式从载脂蛋白E向载脂蛋白III的转变导致轻的极低密度脂蛋白的清除率显著降低(−39%；P<；0.05)，这与载脂蛋白C-III对载脂蛋白E诱导的富含甘油三酯的脂蛋白的清除的拮抗作用相一致。此外，在高甘油三酯血症中，含有载脂蛋白E的富含甘油三酯的脂蛋白的清除速率常数降低，与这些颗粒中载脂蛋白C-III含量增加有关。在高甘油三酯血症中，通过四种动力学扰动，低密度脂蛋白的分布从轻、中低密度脂蛋白转变为高密度低密度脂蛋白：来自含apoC-III的富含甘油三酯的脂蛋白的流量增加，肝脏低密度脂蛋白的分泌模式从轻低密度脂蛋白转变为高密度低密度脂蛋白，从轻低密度脂蛋白和中等低密度脂蛋白向高密度低密度脂蛋白的转化率增加，以及高密度低密度脂蛋白的分解代谢减缓。这些结果支持载脂蛋白C-III在导致高甘油三酯血症的代谢缺陷中的中心作用。在正常的甘油三酯血症患者中，富含甘油三酯的脂蛋白代谢从以迅速清除极低密度脂蛋白为特征的载脂蛋白E为主的系统转变为以富含甘油三酯的脂蛋白清除减少和形成致密的低密度脂蛋白为特征的高甘油三酯血症患者的以载脂蛋白III为主的系统。
Here, we aim to identify defects of apolipoprotein (apo) B lipoprotein metabolism that characterize hypertriglyceridemia, focusing on apoC-III and apoE. We studied the transport of plasma apoB within 21 distinct subfractions as separated by anti–apoC-III and anti–apoE immunoaffinity chromatography and ultracentrifugation in 9 patients with moderate hypertriglyceridemia and 12 normotriglyceridemic control subjects. Hypertriglyceridemia was characterized by a 3-fold higher liver secretion of very low-density lipoprotein (VLDL) that had apoC-III but not apoE and a 50% lower secretion of VLDL with both apoC-III and apoE (both P<0.05). This shift in VLDL secretion pattern from apoE to apoC-III resulted in significantly reduced clearance of light VLDL (−39%; P<0.05), compatible with the antagonizing effects of apoC-III on apoE-induced clearance of triglyceride-rich lipoproteins. In addition, rate constants for clearance were reduced for apoE-containing triglyceride-rich lipoproteins in hypertriglyceridemia, associated with increased apoC-III contents of these particles. LDL distribution shifted from light and medium LDL to dense LDL in hypertriglyceridemia through a quartet of kinetic perturbations: increased flux from apoC-III–containing triglyceride-rich lipoproteins, a shift in liver LDL secretion pattern from light to dense LDL, an increased conversion rate from light and medium LDL to dense LDL, and retarded catabolism of dense LDL. These results support a central role for apoC-III in metabolic defects leading to hypertriglyceridemia. Triglyceride-rich lipoprotein metabolism shifts from an apoE-dominated system in normotriglyceridemic participants characterized by rapid clearance from circulation of VLDL to an apoC-III–dominated system in hypertriglyceridemic patients characterized by reduced clearance of triglyceride-rich lipoproteins and the formation of the dense LDL phenotype.