XBP-1 Remodels Lipid Metabolism to Extend Longevity
XBP-1 Remodels Lipid Metabolism to Extend Longevity
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DOI：
10.1016/j.celrep.2019.06.057
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发表时间：
2019-07-16
期刊：
影响因子：
8.8
通讯作者：
Taylor, Rebecca C.
中科院分区：
文献类型：
--
作者：
Imanikia, Soudabeh;Sheng, Ming;Taylor, Rebecca C.
内质网未折叠蛋白反应（UPR ER）是一种维持分泌通路内稳态、调节糖脂代谢并影响寿命的细胞应激反应。为了探究这种在寿命决定中的作用是否取决于代谢中介，我们对表达UPR ER转录因子XBP-1、XBP-1活性形式的秀丽隐杆线虫进行了代谢分型，发现了许多代谢变化。这包括甘油三酯水平的降低和油酸（OA）水平的增加，油酸是一种与秀丽隐杆线虫寿命延长有关的单不饱和脂肪酸。本研究表明，组成型XBP-1s的表达增加了溶酶体脂肪酶的活性，上调了Delta 9去饱和酶FAT-6的转录，这是XBP-1s诱导的全寿命延长所必需的。饲粮中添加OA可延长野生型动物的寿命，但不能提高表达xbp-1s的动物的寿命，并能增强蛋白质的平衡。这些结果表明，xbp -1对脂质代谢的调节有助于其对蛋白质稳态和寿命的下游影响。
The endoplasmic reticulum unfolded protein response (UPR ER) is a cellular stress response that maintains homeostasis within the secretory pathway, regulates glucose and lipid metabolism, and influences longevity. To ask whether this role in lifespan determination depends upon metabolic intermediaries, we metabotyped C. elegans expressing the active form of the UPR ER transcription factor XBP-1, XBP-1s, and found many metabolic changes. These included reduced levels of triglycerides and increased levels of oleic acid (OA), a monounsaturated fatty acid associated with lifespan extension in C. elegans. Here, we show that constitutive XBP-1s expression increases the activity of lysosomal lipases and upregulates transcription of the Delta 9 desaturase FAT-6, which is required for the full lifespan extension induced by XBP-1s. Dietary OA supplementation increases the lifespan of wild-type, but not xbp-1s-expressing animals and enhances proteostasis. These results suggest that modulation of lipid metabolism by XBP-1s contributes to its downstream effects on protein homeostasis and longevity.