A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange.
A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange.
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DOI：
10.1038/nature07349
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发表时间：
2008-11-13
期刊：
影响因子：
64.8
通讯作者：
Montminy, Marc
中科院分区：
文献类型：
--
作者：
Liu, Yi;Dentin, Renaud;Chen, Danica;Hedrick, Susan;Ravnskjaer, Kim;Schenk, Simon;Milne, Jill;Meyers, David J.;Cole, Phil;Yates, John, III;Olefsky, Jerrold;Guarente, Leonard;Montminy, Marc
在早期禁食期间，骨骼肌蛋白水解的增加释放游离氨基酸，用于响应胰高血糖素的肝再生。在禁食的后期蛋白质保留阶段，肝脏的葡萄糖输出减少，此时肝脏产生的酮体为葡萄糖依赖性组织提供补偿性燃料。胰高血糖素通过触发CREB调节的转录辅激活因子2（CRTC 2;也称为TORC 2）的去磷酸化和核转位来刺激促胰岛素生成程序，而胰岛素信号传导的平行减少通过叉头盒O 1（FOXO 1）的去磷酸化和核穿梭来增强促胰岛素生成基因表达。在这里，我们表明，一个禁食诱导开关，组蛋白乙酰转移酶（HAT）P300和营养敏感脱乙酰酶Sirtuin 1（SIRT 1）组成，通过连续诱导CRTC 2和FOXO 1维持能量平衡。在胰高血糖素诱导后，CRTC 2通过与P300的结合刺激了促血管生成基因的表达，我们在这里显示，在禁食期间，P300也被Ser 89的去磷酸化激活。反过来，P300通过在Lys 628处乙酰化CRTC 2来增加肝CRTC 2活性，Lys 628是CRTC 2在被E3连接酶组成型光形态发生蛋白（COP 1）泛素化后降解的靶位点。胰高血糖素的作用在晚期禁食期间减弱，此时CRTC 2由于SIRT 1介导的去乙酰化而下调，并且FOXO 1支持促胰岛素生成程序的表达。通过肝脏特异性敲除SIRT 1基因或给予SIRT 1拮抗剂来破坏SIRT 1活性，可增加CRTC 2活性和葡萄糖输出，而暴露于SIRT 1激动剂则可降低CRTC 2活性和葡萄糖输出。考虑到FOXO 1及其共激活剂过氧化物酶体增殖物激活受体γ共激活因子1 α（PGC-1α）被SIRT 1激活剂相互激活，我们的研究结果说明了禁食期间两种促血管生成调节剂的交换如何维持能量平衡。
During early fasting, increases in skeletal muscle proteolysis liberate free amino acids for hepatic gluconeogenesis in response to pancreatic glucagon. Hepatic glucose output diminishes during the late protein-sparing phase of fasting, when ketone body production by the liver supplies compensatory fuel for glucose-dependent tissues. Glucagon stimulates the gluconeogenic program by triggering the dephosphorylation and nuclear translocation of the CREB regulated transcription coactivator 2 (CRTC2; also known as TORC2), while parallel decreases in insulin signaling augment gluconeogenic gene expression through the de-phosphorylation and nuclear shuttling of Forkhead Box O1 (FOXO1). Here we show that a fasting-inducible switch, consisting of the histone acetyl-transferase (HAT) P300 and the nutrient-sensing deacetylase Sirtuin 1 (SIRT1), maintains energy balance through the sequential induction of CRTC2 and FOXO1. Following glucagon induction, CRTC2 stimulated gluconeogenic gene expression through an association with P300, which we show here is also activated by de-phosphorylation at Ser89 during fasting. In turn, P300 increased hepatic CRTC2 activity by acetylating it at Lys628, a site that also targets CRTC2 for degradation following its ubiquitination by the E3 ligase Constitutive Photomorphogenic Protein (COP1). Glucagon effects were attenuated during late fasting, when CRTC2 was down-regulated due to SIRT1-mediated deacetylation and when FOXO1 supported expression of the gluconeogenic program. Disrupting SIRT1 activity, by liver-specific knockout of the SIRT1 gene or by administration of SIRT1 antagonist, increased CRTC2 activity and glucose output, while exposure to SIRT1 agonists reduced them. In view of the reciprocal activation of FOXO1 and its coactivator peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1α) by SIRT1 activators, our results illustrate how the exchange of two gluconeogenic regulators during fasting maintains energy balance.
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DOI：
10.1016/j.bbrc.2005.09.169
发表时间：
2005-12-02
影响因子：
3.1
作者：
Gan, LX;Han, YS;Quirion, R
通讯作者：
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影响因子：
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作者：
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作者：
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通讯作者：
RUDERMAN, NB
影响因子：
11.4
作者：
Ravnskjaer, Kim;Kester, Henri;Montminy, Marc
通讯作者：
Montminy, Marc