IRE1β inhibits chylomicron production by selectively degrading MTP mRNA
IRE1β inhibits chylomicron production by selectively degrading MTP mRNA
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DOI：
10.1016/j.cmet.2008.03.005
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发表时间：
2008-05-01
期刊：
影响因子：
29
通讯作者：
Hussain, M. Mahmood
中科院分区：
文献类型：
--
作者：
Iqbal, Jahangir;Dai, Kezhi;Hussain, M. Mahmood
微粒体甘油三酯转移蛋白（MTP）需要在肠细胞内质网（ER）中组装乳糜微粒。我们探索了内质网应激蛋白，肌醇要求酶1 β (IRE1 β)在调节这一过程中的作用。高胆固醇和高脂肪饮食降低了野生型小鼠肠道IRE1 β mRNA的表达。饲喂高胆固醇和高脂肪饮食的Ire1b（-/-）小鼠出现了更明显的高脂血症，因为这些小鼠分泌更多的乳糜微粒，表达更多的肠道MTP，尽管没有肝脏MTP，但比野生型小鼠。从胆固醇喂养的Ireb（-/-）小鼠分离的原代肠细胞中乳糜微粒分泌和MTP表达也增加。内质网应激与MTP表达无相关性。相反，细胞培养研究显示IRE1 β，而不是其普遍存在的同系物IRE1 α，通过增加转录后降解来降低MTP mRNA。相反，IRE1 β的敲低会增强MTP的表达。这些研究表明IRE1 β在调节MTP和乳糜微粒的产生中起作用。
Microsomal triglyceride transfer protein (MTP) is needed to assemble chylomicrons in the endoplasmic reticulum (ER) of enterocytes. We explored the role of an ER stress protein, inositol-requiring enzyme 1 beta (IRE1 beta), in regulating this process. High-cholesterol and high-fat diets decreased intestinal IRE1 beta mRNA in wild-type mice. Ire1b(-/-) mice fed high-cholesterol and high-fat diets developed more pronounced hyperlipidemia because these mice secreted more chylomicrons and expressed more intestinal MTP, though not hepatic MTP, than wildtype mice did. Chylomicron secretion and MTP expression also were increased in primary enterocytes isolated from cholesterol-fed Ireb(-/-) mice. There was no correlation between ER stress and MTP expression. Instead, cell culture studies revealed that IRE1 beta, but not its ubiquitous homolog IRE1 alpha, decreased MTP mRNA through increased posttranscriptional degradation. Conversely, knockdown of IRE1 beta enhanced MTP expression. These studies show that IRE1 beta plays a role in regulating MTP and in chylomicron production.