Emergency Intensive Care Unit, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, China.
Emergency Intensive Care Unit, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, China.
Redox Biol. 2018 Jun;16:87-96. doi: 10.1016/j.redox.2018.01.013. Epub 2018 Feb 1.
Liver coordinates a series of metabolic adaptations to maintain systemic energy balance and provide adequate nutrients for critical organs, tissues and cells during starvation. However, the mediator(s) implicated in orchestrating these fasting-induced adaptive responses and the underlying molecular mechanisms are still obscure. Here we show that hepatic growth differentiation factor 15 (GDF15) is regulated by IRE1α-XBP1s branch and promotes hepatic fatty acids β-oxidation and ketogenesis upon fasting. GDF15 expression was exacerbated in liver of mice subjected to long-term fasted or ketogenic diet feeding. Abrogation of hepatic Gdf15 dramatically attenuated hepatic β-oxidation and ketogenesis in fasted mice or mice with STZ-initiated type I diabetes. Further study revealed that XBP1s activated Gdf15 transcription via binding to its promoter. Elevated GDF15 in liver reduced lipid accumulation and impaired NALFD development in obese mice through enhancing fatty acids oxidation in liver. Therefore, our results demonstrate a novel and critical role of hepatic GDF15 activated by IRE1α-XBP1s branch in regulating adaptive responses of liver upon starvation stress.
肝脏协调一系列代谢适应，以维持全身能量平衡，并在饥饿时为关键器官、组织和细胞提供足够的营养。然而，在协调这些饥饿诱导的适应性反应及其潜在的分子机制中涉及的介质仍然不清楚。在这里，我们表明肝生长分化因子 15 (GDF15) 受到 IRE1α-XBP1s 分支的调节，并在禁食时促进肝脏脂肪酸的β氧化和酮生成。长期禁食或生酮饮食喂养的小鼠肝脏中 GDF15 的表达加剧。肝脏 Gdf15 的缺失显著减弱了禁食小鼠或 STZ 诱导的 I 型糖尿病小鼠的肝β氧化和酮生成。进一步的研究表明，XBP1s 通过结合其启动子激活 Gdf15 的转录。肝脏中升高的 GDF15 通过增强肝脏中脂肪酸的氧化，减少肥胖小鼠肝脏中的脂质积累并改善 NALFD 的发展。因此，我们的研究结果表明，IRE1α-XBP1s 分支激活的肝脏 GDF15 在调节饥饿应激下肝脏的适应性反应中发挥了新的和关键作用。
