Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Current address: Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, 42988, Republic of Korea.
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Mol Metab. 2018 Jan;7:119-131. doi: 10.1016/j.molmet.2017.10.010. Epub 2017 Oct 28.
Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) promotes hepatic gluconeogenesis by activating HNF4α and FoxO1. PGC-1α expression in the liver is highly elevated in obese and diabetic conditions, leading to increased hepatic glucose production. We previously showed that the spliced form of X-box binding protein 1 (XBP1s) suppresses FoxO1 activity and hepatic gluconeogenesis. The shared role of PGC-1α and XBP1s in regulating FoxO1 activity and gluconeogenesis led us to investigate the probable interaction between PGC-1α and XBP1s and its role in glucose metabolism.
We investigated the biochemical interaction between PGC-1α and XBP1s and examined the role of their interaction in glucose homeostasis using animal models.
We show that PGC-1α interacts with XBP1s, which plays an anti-gluconeogenic role in the liver by suppressing FoxO1 activity. The physical interaction between PGC-1α and XBP1s leads to suppression of XBP1s activity rather than its activation. Upregulating PGC-1α expression in the liver of lean mice lessens XBP1s protein levels, and reducing PGC-1α levels in obese and diabetic mouse liver restores XBP1s protein induction.
Our findings reveal a novel function of PGC-1α as a suppressor of XBP1s function, suggesting that hepatic PGC-1α promotes gluconeogenesis through multiple pathways as a co-activator for HNF4α and FoxO1 and also as a suppressor for anti-gluconeogenic transcription factor XBP1s.
过氧化物酶体增殖物激活受体 γ（PPARγ）共激活因子 1α（PGC-1α）通过激活 HNF4α 和 FoxO1 促进肝糖异生。肥胖和糖尿病状态下肝脏中 PGC-1α 的表达显著升高，导致肝葡萄糖生成增加。我们之前的研究表明，X 盒结合蛋白 1（XBP1）的剪接形式（XBP1s）抑制 FoxO1 活性和肝糖异生。PGC-1α 和 XBP1s 在调节 FoxO1 活性和糖异生中的共同作用促使我们研究 PGC-1α 和 XBP1s 之间可能的相互作用及其在葡萄糖代谢中的作用。
我们研究了 PGC-1α 和 XBP1s 之间的生化相互作用，并使用动物模型研究了它们相互作用在葡萄糖稳态中的作用。
我们表明 PGC-1α 与 XBP1s 相互作用，XBP1s 通过抑制 FoxO1 活性在肝脏中发挥抗糖异生作用。PGC-1α 和 XBP1s 之间的物理相互作用导致 XBP1s 活性的抑制，而不是其激活。在瘦鼠肝脏中上调 PGC-1α 的表达会降低 XBP1s 蛋白水平，而在肥胖和糖尿病鼠肝脏中降低 PGC-1α 水平会恢复 XBP1s 蛋白诱导。
我们的研究结果揭示了 PGC-1α 作为 XBP1s 功能抑制剂的新功能，表明肝 PGC-1α 通过作为 HNF4α 和 FoxO1 的共激活因子以及作为抗糖异生转录因子 XBP1s 的抑制剂来促进糖异生的多个途径。
