Hepatic VLDL secretion: DGAT1 determines particle size but not particle number, which can be supported entirely by DGAT2.
Hepatic VLDL secretion: DGAT1 determines particle size but not particle number, which can be supported entirely by DGAT2.
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DOI：
10.1194/jlr.m089300
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发表时间：
2019-01
影响因子：
6.5
通讯作者：
Zammit VA
中科院分区：
文献类型：
--
作者：
Irshad Z;Chmel N;Adya R;Zammit VA
我们研究了是否，鉴于其活性表达在内质网（ER;双膜拓扑结构）的两个方面，二酰基甘油酰基转移酶1（DGAT 1）在确定肝脏分泌的VLDL颗粒的甘油三酯（TAG）含量中起着独特的作用。在肝细胞中特异性消融DGAT 1基因的小鼠（DGAT 1-LKO小鼠）在Triton 1339处理后1小时血浆中具有相同数量的VLDL颗粒（apoB浓度），但这些颗粒的大小约为对照小鼠分泌的VLDL颗粒的一半，并且具有成比例降低的TAG含量，胆固醇和胆固醇酯含量正常。从16 h禁食对照和DAGT 1-LKO小鼠制备的纯化微粒体组分的分析表明，后者ER中的TAG/蛋白质比显著较低。这些肝脏的电子显微照片显示，DGAT 1-LKO小鼠的肝脏没有显示出对照肝脏所显示的光滑ER的脂质含量增加。DGAT 1和DGAT 2特异性抑制剂对HepG 2细胞apoB分泌的影响表明，DGAT 1不是apoB分泌所必需的，并且证明了两种酶支持apoB分泌的能力的冗余。因此，我们的研究结果表明，DGAT 1是必不可少的完全脂质化和成熟的极低密度脂蛋白颗粒内的内腔的ER，符合其双重拓扑结构内的ER膜。在小鼠中，DGAT 2可以支持apoB分泌（颗粒数），即使在不存在DGAT 1的情况下，完全VLDL脂化的TAG可用性受到限制。
We investigated whether, in view of its activity being expressed on both aspects of the endoplasmic reticulum (ER; dual membrane topology), diacylglycerol acyltransferase 1 (DGAT1) plays a distinctive role in determining the triglyceride (TAG) content of VLDL particles secreted by the liver. Mice in which the DGAT1 gene was specifically ablated in hepatocytes (DGAT1-LKO mice) had the same number of VLDL particles (apoB concentration) in the plasma 1 h after Triton 1339 treatment, but these particles were approximately half the size of VLDL particles secreted by control mice and had a proportionately decreased content of TAG, with normal cholesterol and cholesteryl ester contents. Analyses of purified microsomal fractions prepared from 16 h fasted control and DAGT1-LKO mice showed that the TAG/protein ratio in the ER was significantly lower in the latter. Electron micrographs of these livers showed that those from DGAT1-LKO mice did not show the increased lipid content of the smooth ER shown by control livers. The effects of DGAT1- and DGAT2-specific inhibitors on apoB secretion by HepG2 cells showed that DGAT1 is not indispensable for apoB secretion and demonstrated redundancy in the ability of the two enzymes to support apoB secretion. Therefore, our findings show that DGAT1 is essential for the complete lipidation and maturation of VLDL particles within the lumen of the ER, consistent with its dual topology within the ER membrane. In the mouse, DGAT2 can support apoB secretion (particle number) even when TAG availability for full VLDL lipidation is restricted in the absence of DGAT1.