Liver-specific dysregulation of clock-controlled output signal impairs energy metabolism in liver and muscle
Liver-specific dysregulation of clock-controlled output signal impairs energy metabolism in liver and muscle
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DOI：
10.1016/j.bbrc.2020.11.066
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发表时间：
2021-01-01
影响因子：
3.1
通讯作者：
Tanizawa, Yukio
中科院分区：
文献类型：
--
作者：
Matsumura, Takuro;Ohta, Yasuharu;Tanizawa, Yukio
肝脏是动物在进食和禁食状态之间转换期间维持代谢稳态的主要器官。包括肝脏在内的外周组织的昼夜节律振荡与进食-禁食周期有关。我们产生了肝细胞特异性E4 BP 4，D-box负调控因子，过表达的转基因小鼠。肝特异性E4 BP 4过表达也通过腺病毒基因转移实现。有趣的是，肝脏E4 BP 4过表达诱导显著的胰岛素抵抗，这是由DBP，一个竞争性的D-box阳性调节剂，过表达拯救。在基础条件下，肝细胞E4 BP 4转基因小鼠表现出增加的肝细胞生成和减少的AKT磷酸化。在肌肉中，胰岛素刺激后AKT磷酸化受损。这种肌肉胰岛素抵抗与肝脏游离脂肪酸流量增加和非活动期脂肪酸作为能量来源的利用减少有关。E4 BP 4是一种时钟控制的输出基因，是肝脏中的关键代谢调节因子，在进食-禁食周期中调节肝脏和肌肉的代谢以及胰岛素敏感性。它的调整对于预防代谢紊乱至关重要。(C)2020爱思唯尔公司All rights reserved.
The liver is the major organ maintaining metabolic homeostasis in animals during shifts between fed and fasted states. Circadian oscillations in peripheral tissues including the liver are connected with feeding-fasting cycles. We generated transgenic mice with hepatocyte specific E4BP4, D-box negative regulator, overexpression. Liver-specific E4BP4 overexpression was also achieved by adenoviral gene transfer. Interestingly, hepatic E4BP4 overexpression induced marked insulin resistance, that was rescued by DBP, a competing D-box positive regulator, overexpression. At basal conditions hepatocyte E4BP4 transgenic mice exhibited increased gluconeogenesis with reduced AKT phosphorylation in liver. In muscle, AKT phosphorylation was impaired after insulin stimulation. Such muscle insulin resistance was associated with elevated free fatty acid flux from the liver and reduced fatty acid utilization as an energy source during the inactive phase. E4BP4, one of the clock-controlled output genes, are key metabolic regulators in liver adjusting liver and muscle metabolism and insulin sensitivity in the feeding-fasting cycles. Its tuning is critical for preventing metabolic disorders. (C) 2020 Elsevier Inc. All rights reserved.