The Xbp1s/GalE axis links ER stress to postprandial hepatic metabolism
The Xbp1s/GalE axis links ER stress to postprandial hepatic metabolism
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DOI：
10.1172/jci62819
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发表时间：
2013-01-01
影响因子：
15.9
通讯作者：
Scherer, Philipp E.
中科院分区：
文献类型：
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作者：
Deng, Yingfeng;Wang, Zhao V.;Scherer, Philipp E.
餐后，肝脏经历了广泛的代谢重编程，这是从葡萄糖产生转换为葡萄糖同化所必需的。在再喂食时，未折叠蛋白质反应（UPR）被迅速激活，尽管只是短暂的。UPR的激活导致蛋白质翻译的停止、伴侣蛋白表达的增加和ER介导的蛋白质降解的增加，但尚不清楚UPR如何参与餐后转换到替代燃料来源。UPR信号通路的肌醇需要酶1（IRE 1）分支的激活触发转录因子Xbp 1 s的表达。使用肝脏特异性诱导Kbp 1 s表达的小鼠模型，我们证明Xbp 1 s足以引起餐后状态的代谢开关特征，即使在没有热量流入的情况下。从机制上讲，我们确定UDP-半乳糖-4-差向异构酶（GalE）作为Xbp 1 s的直接转录靶点，并作为这种效应的关键介质。我们的研究结果提供的证据表明，Xbp 1 s/GslE途径的功能作为一种新的调节连接UP R的特征餐后肝细胞的代谢变化。
Postprandially, the liver experiences an extensive metabolic reprogramming that is required for the switch from glucose production to glucose assimilation. Upon refeeding, the unfolded protein response (UPR) is rapidly, though only transiently, activated. Activation of the UPR results in a cessation of protein translation, increased chaperone expression, and increased ER-mediated protein degradation, but it is not clear how the UPR is involved in the postprandial switch to alternate fuel sources. Activation of the inositol-requiring enzyme 1 (IRE1) branch of the UPR signaling pathway triggers expression of the transcription factor Xbp1s. Using a mouse model with liver-specific inducible Kbp1s expression, we demonstrate that Xbp1s is sufficient to provoke a metabolic switch characteristic of the postprandial state, even in the absence of caloric influx. Mechanistically, we identified UDP-galactose-4-epimerase (GalE) as a direct transcriptional target of Xbp1s and as the key mediator of this effect. Our results provide evidence that the Xbp1s/GslE pathway functions as a novel regulatory nexus connecting the UP R to the characteristic postprandial metabolic changes in hepatocytes.