Hepatic PHD2/HIF-1 axis is involved in postexercise systemic energy homeostasis
Hepatic PHD2/HIF-1 axis is involved in postexercise systemic energy homeostasis
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肝脏 PHD2/HIF-1α 轴参与运动后全身能量稳态
DOI：
10.1096/fj.201701139r
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发表时间：
2018-09-01
期刊：
影响因子：
4.8
通讯作者：
Hu, Yi-Ping
中科院分区：
文献类型：
--
作者：
Luo, Beibei;Xiang, Dao;Hu, Yi-Ping
运动在预防和治疗慢性肝病及相关代谢紊乱方面发挥着重要作用。单次运动可引起组织血流量重新分配，减少内脏循环，导致胃肠系统和肝脏生理性缺氧。转录因子低氧诱导因子-1(HIF-1)及其调节因子Pro-羟基酶2(PHD2)通过调节肝脏下游基因的表达水平，在肝脏对氧通量的反应中发挥关键作用。我们假设运动增加了肝脏中HIF-1的水平，肝脏PHD2/HIF-1轴参与了运动后全身能量平衡的恢复。通过持续的氧耗量、二氧化碳的产生、食物和水的摄入量，以及用代谢室检测体力活动，我们观察到一次30分钟的游泳运动可以增强小鼠全身的能量代谢。通过使用非侵入性生物发光成像ROSA26氧依赖结构域LUC小鼠模型，我们揭示了运动增加了体内肝脏中HIF的水平。腹腔注射PHD抑制剂二甲氧甘氨酸可模拟运动诱导的HIF增加，而HIF-1抑制剂PX-478可阻断这一效应。接下来，我们构建了白蛋白-Cre介导、肝细胞特异性HIF1a和PHD2缺失的肝脏特异性基因敲除(LKO)小鼠模型。与对照组相比，HIF1a-LKO和PHD2-LKO小鼠表现出不同的肝脏代谢相关基因表达谱模式。此外，HIF1a-LKO小鼠在运动后未能恢复全身能量平衡。总而言之，目前的研究表明，单次运动会破坏全身能量平衡，增加肝脏中HIF-1的水平。这些发现也为肝脏PHD2/HIF-1轴参与运动后全身代谢动态平衡提供了证据。罗，B.，向，丁，吴，丁，刘，C，方，Y.，陈，P，胡，Y.-P。肝脏PHD2/HIF-1轴参与运动后全身能量平衡。
Exercise plays an important role in the prevention and treatment of chronic liver disease and associated metabolic disorders. A single bout of exercise induces tissue blood flow redistribution, which decreases splanchnic circulation and leads to physiologic hypoxia in the gastrointestinal system and liver. The transcription factor, hypoxia inducible factor-1 (HIF-1), and its regulator, prolylhydroxylase 2 (PHD2), play pivotal roles in the response to oxygen flux by regulating downstream gene expression levels in the liver. We hypothesized that exercise increases the HIF-1 levels in the liver, and that the hepatic PHD2/HIF-1 axis is involved in postexercise restoration of systemic energy homeostasis. Through constant O-2 consumption, CO2 production, food and water intake, and physical activity detection with metabolic chambers, we observed that one 30-min session of swimming exercise enhances systemic energy metabolism in mice. By using the noninvasive bioluminescence imaging ROSA26 oxygen-dependent domain Luc mouse model, we reveal that exercise increases in vivo HIF levels in the liver. Intraperitoneal injections of the PHD inhibitor, dimethyloxalylglycine, mimicked exercise-induced HIF increase, whereas the HIF-1 inhibitor, PX-478, blocked this effect. We next constructed liver-specific knockout (LKO) mouse models with albumin-Cre-mediated, hepatocyte-specific Hif1a and Phd2 deletion. Compared with their controls, Hif1a-LKO and Phd2-LKO mice exhibited distinct patterns of hepatic metabolism-related gene expression profiles. Moreover, Hif1a-LKO mice failed to restore systemic energy homeostasis after exercise. In conclusion, the current study demonstrates that a single bout of exercise disrupts systemic energy homeostasis, increasing the HIF-1 levels in the liver. These findings also provide evidence that the hepatic PHD2/HIF-1 axis is involved in postexercise systemic metabolic homeostasis.Luo, B., Xiang, D., Wu, D., Liu, C., Fang, Y., Chen, P., Hu, Y.-P. Hepatic PHD2/HIF-1 axis is involved in postexercise systemic energy homeostasis.