PGC-1α functions as a co-suppressor of XBP1s to regulate glucose metabolism.
PGC-1α functions as a co-suppressor of XBP1s to regulate glucose metabolism.
复制标题
PGC-1α充当XBP1的共抑制剂，以调节葡萄糖代谢。
DOI：
10.1016/j.molmet.2017.10.010
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发表时间：
2018-01
影响因子：
8.1
通讯作者：
Ozcan U
中科院分区：
文献类型：
--
作者：
Lee J;Salazar Hernández MA;Auen T;Mucka P;Lee J;Ozcan U
过氧化物酶体增殖物激活受体γ（PPARγ）共激活因子-1 α（PGC-1α）通过激活HNF 4 α和FoxO 1促进肝细胞的生成。在肥胖和糖尿病条件下，肝脏中的PGC-1α表达高度升高，导致肝脏葡萄糖产生增加。我们以前表明，剪接形式的X-box结合蛋白1（XBP 1 s）抑制FoxO 1的活性和肝细胞生成。PGC-1α和XBP 1 s在调节FoxO 1活性和胚胎发生中的共同作用使我们研究了PGC-1α和XBP 1 s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XBP 1 s之间的生物化学相互作用，并使用动物模型研究了它们在葡萄糖稳态中的相互作用。我们发现PGC-1α与XBP 1 s相互作用，通过抑制FoxO 1活性在肝脏中发挥抗肿瘤作用。PGC-1α和XBP 1 s之间的物理相互作用导致XBP 1 s活性的抑制而不是其激活。上调瘦小鼠肝脏中的PGC-1α表达可降低XBP 1 s蛋白水平，降低肥胖和糖尿病小鼠肝脏中的PGC-1α水平可恢复XBP 1 s蛋白诱导。我们的研究结果揭示了PGC-1α作为XBP 1 s功能抑制剂的新功能，表明肝脏PGC-1α作为HNF 4 α和FoxO 1的共激活剂以及作为抗凋亡转录因子XBP 1 s的抑制剂通过多种途径促进凋亡发生。XBP 1 s抑制FoxO 1活性和肝脏新生。PGC-1α与XBP 1 s物理相互作用，并在肝脏中作为XBP 1 s的共抑制剂发挥作用。PGC-1α对XBP 1 s活性的抑制导致肥胖小鼠的葡萄糖稳态受损。肝脏PGC-1α作为共激活剂和共抑制剂促进肝脏新生。
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. XBP1s suppresses FoxO1 activity and hepatic gluconeogenesis. PGC-1α physically interacts with XBP1s and functions as a co-suppressor of XBP1s in the liver. The suppression of XBP1s activity by PGC-1α leads to impaired glucose homeostasis in obese mice. Hepatic PGC-1α promotes gluconeogenesis as a co-activator and also as a co-suppressor.
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DOI：
10.1001/jama.2014.732
发表时间：
2014-02-26
期刊：
JAMA
影响因子：
--
作者：
Ogden CL;Carroll MD;Kit BK;Flegal KM
通讯作者：
Flegal KM
影响因子：
5.3
作者：
Knutti, D;Kaul, A;Kralli, A
通讯作者：
Kralli, A
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D
影响因子：
16
作者：
Higgins, Renee;Gendron, Joshua M.;Rising, Lisa;Mak, Raymond;Webb, Kristofor;Kaiser, Stephen E.;Zuzow, Nathan;Riviere, Paul;Yang, Bing;Fenech, Emma;Tang, Xin;Lindsay, Scott A.;Christianson, John C.;Hampton, Randolph Y.;Wasserman, Steven A.;Bennett, Eric J.
通讯作者：
Bennett, Eric J.
影响因子：
15.9
作者：
Deng, Yingfeng;Wang, Zhao V.;Scherer, Philipp E.
通讯作者：
Scherer, Philipp E.