Hepatic Crtc2 controls whole body energy metabolism via a miR-34a-Fgf21 axis.
Hepatic Crtc2 controls whole body energy metabolism via a miR-34a-Fgf21 axis.
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DOI：
10.1038/s41467-017-01878-6
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发表时间：
2017-11-30
影响因子：
16.6
通讯作者：
Koo SH
中科院分区：
文献类型：
--
作者：
Han HS;Choi BH;Kim JS;Kang G;Koo SH
肝脏在控制哺乳动物体内能量平衡方面起着至关重要的作用，尽管它影响其他外周组织的确切机制尚未得到解决。在这里，我们表明Creb调节转录辅激活因子（Crtc）2是全身能量代谢的主要调节因子。crtc 2肝脏特异性敲除降低血糖水平，改善葡萄糖和胰岛素耐受性。肝脏特异性基因敲除小鼠显示出增加的能量消耗，脂肪库中的脂滴较小。Crtc 2肝脏特异性基因敲除小鼠的血浆和肝脏Fgf 21水平均升高，这是由于Creb/Crtc 2调控的miR-34 a表达降低以及Sirt 1和Pparα的诱导所致。miR-34 a的异位表达逆转了基因敲除肝脏中的代谢变化。我们认为Creb/Crtc 2通过诱导miR-34 a负性调节Sirt 1/Pparα/Fgf 21轴。CREB调节的转录辅激活因子2（CRTC 2）与葡萄糖和脂质稳态的调节有关。Han等人在本文中表明，Creb/Crtc 2通过抑制mi-R34的表达来调节脂质和葡萄糖代谢，mi-R34反过来又抑制Sirt 1和PPARα的表达，从而抑制Fgf 21水平。
Liver plays a crucial role in controlling energy homeostasis in mammals, although the exact mechanism by which it influences other peripheral tissues has yet to be addressed. Here we show that Creb regulates transcriptional co-activator (Crtc) 2 is a major regulator of whole-body energy metabolism. Crtc2 liver-specific knockout lowers blood glucose levels with improved glucose and insulin tolerance. Liver-specific knockout mice display increased energy expenditure with smaller lipid droplets in adipose depots. Both plasma and hepatic Fgf21 levels are increased in Crtc2 liver-specific knockout mice, as a result of the reduced miR-34a expression regulated by Creb/Crtc2 and the induction of Sirt1 and Pparα. Ectopic expression of miR-34a reverses the metabolic changes in knockout liver. We suggest that Creb/Crtc2 negatively regulates the Sirt1/Pparα/Fgf21 axis via the induction of miR-34a under diet-induced obesity and insulin-resistant conditions. CREB-regulated transcription coactivator 2, CRTC2, has been associated with regulation of glucose and lipid homeostasis. Here Han et al. show that Creb/Crtc2 modulates lipid and glucose metabolism by inhibiting the expression of mi-R34 that, in turn, represses the expression of Sirt1 and PPARα and consequently Fgf21 levels.
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影响因子：
29
作者：
Le Lay J;Tuteja G;White P;Dhir R;Ahima R;Kaestner KH
通讯作者：
Kaestner KH
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
5.7
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通讯作者：
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通讯作者：
Kemper JK
影响因子：
8.1
作者：
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通讯作者：
Potthoff MJ