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首页> 外文期刊>Nature >A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange
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A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange

机译：空腹诱导开关通过激活剂/共激活剂交换调节糖异生

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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 signalling augment gluconeogenic gene expression through the dephosphorylation and nuclear shuttling of forkhead box O1 (FOXO1). Here we show that a fasting-inducible switch, consisting of the histone acetyltrans-ferase p300 and the nutrient-sensing deacetylase sirtuin 1 (SIRT1), maintains energy balance in mice through the sequential induction of CRTC2 and FOXO1. After glucagon induction, CRTC2 stimulated gluconeogenic gene expression by an association with p300, which we show here is also activated by dephosphorylation at Ser 89 during fasting. In turn, p300 increased hepatic CRTC2 activity by acetylat-ing it at Lys 628, a site that also targets CRTC2 for degradation after its ubiquitination by the E3 ligase constitutive photomorphogenic protein (COP1). Glucagon effects were attenuated during late fasting, when CRTC2 was downregulated owing 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 a SIRT1 antagonist, increased CRTC2 activity and glucose output, whereas exposure to SIRT1 agonists reduced them. In view of the reciprocal activation of FOXO1 and its coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α, encoded by Ppargc1a) by SIRT1 activators, our results illustrate how the exchange of two gluconeogenic regulators during fasting maintains energy balance.
机译：在早期禁食期间，骨骼肌蛋白水解的增加会释放游离氨基酸，以响应胰高血糖素引起肝糖异生。在禁食的后期蛋白质保留阶段，当肝脏产生的酮体为葡萄糖依赖性组织提供代偿性燃料时，肝葡萄糖输出减少。胰高血糖素通过触发CREB调控的转录共激活因子2（CRTC2；也称为TORC2）的去磷酸化和核易位来刺激糖异生程序，而胰岛素信号的平行降低则通过叉头盒O1（FOXO1）的去磷酸化和核穿梭来增强糖异生基因的表达。 ）。在这里，我们显示了由组蛋白乙酰转移酶p300和营养敏感的脱乙酰基酶沉默调节蛋白1（SIRT1）组成的禁食诱导开关，通过依次诱导CRTC2和FOXO1来维持小鼠的能量平衡。胰高血糖素诱导后，CRTC2通过与p300的结合刺激了糖异生基因的表达，我们在这里展示了禁食期间Ser 89的去磷酸化也激活了它。反过来，p300通过在Lys 628处对它进行乙酰化而增加了肝CRTC2的活性，该位点在被E3连接酶组成型光形态发生蛋白（COP1）泛素化后也靶向CRTC2降解。当SITC1介导的脱乙酰基作用下CRTC2下调以及FOXO1支持糖原异生程序的表达时，在禁食后期，胰高血糖素的作用减弱。通过肝脏特异性敲除Sirt1基因或施用SIRT1拮抗剂破坏SIRT1活性，会增加CRTC2活性和葡萄糖输出，而暴露于SIRT1激动剂则会降低它们。鉴于SIRT1激活剂对FOXO1及其共激活因子过氧化物酶体增殖物激活的受体-γ共激活因子-1α（PGC-1α，由Ppargc1a编码）的相互激活，我们的结果说明了禁食期间两个糖异生调节剂的交换如何维持能量平衡。

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