MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK.
Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Cambridge, UK.
Cell Rep. 2019 Jul 16;28(3):581-589.e4. doi: 10.1016/j.celrep.2019.06.057.
The endoplasmic reticulum unfolded protein response (UPR) 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 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 Δ9 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.
内质网未折叠蛋白反应 (UPR) 是一种细胞应激反应，可维持分泌途径中的内稳态，调节葡萄糖和脂质代谢，并影响寿命。为了探究这种在寿命决定中的作用是否依赖于代谢中间产物，我们对表达 UPR 转录因子 XBP-1 的活性形式 XBP-1s 的秀丽隐杆线虫进行了代谢分型，发现了许多代谢变化。这些变化包括甘油三酯水平降低和油酸 (OA) 水平升高，OA 是一种与秀丽隐杆线虫寿命延长相关的单不饱和脂肪酸。在这里，我们表明组成型 XBP-1s 表达增加了溶酶体脂肪酶的活性，并上调了 Δ9 去饱和酶 FAT-6 的转录，FAT-6 对于 XBP-1s 诱导的全长寿命延长是必需的。OA 饮食补充可延长野生型动物的寿命，但不能延长 xbp-1s 表达动物的寿命，并且可增强蛋白质稳态。这些结果表明，XBP-1s 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。
