Reciprocal regulation of carbon monoxide metabolism and the circadian clock
Reciprocal regulation of carbon monoxide metabolism and the circadian clock
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DOI：
10.1038/nsmb.3331
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发表时间：
2017-01-01
影响因子：
16.8
通讯作者：
Kramer, Achim
中科院分区：
文献类型：
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作者：
Klemz, Roman;Reischl, Silke;Kramer, Achim
生物钟是细胞自主振荡器，在广泛的生理、代谢和行为过程中调节日常节律。代谢信号的反馈，如氧化还原状态，NAD(+)/NADH和AMP/ADP比率，或血红素，调节昼夜节律，从而优化整个24小时周期的能量利用。我们表明，产生信号分子一氧化碳（CO）的节律性血红素降解是正常昼夜节律和昼夜代谢输出所必需的。CO通过减弱CLOCK BMAL1与目标启动子的结合来抑制昼夜节律转录。在哺乳动物细胞和果蝇中，产生co的血红素加氧酶的药理抑制或基因耗竭会破坏正常的日常循环。在小鼠肝细胞中，CO生成的抑制导致CLOCK bmal1依赖性昼夜节律基因表达的全局上调和葡萄糖代谢失调。总之，我们的研究结果表明，CO代谢是基本生物钟机制、代谢和行为之间的重要联系。
Circadian clocks are cell-autonomous oscillators regulating daily rhythms in a wide range of physiological, metabolic and behavioral processes. Feedback of metabolic signals, such as redox state, NAD(+)/NADH and AMP/ADP ratios, or heme, modulate circadian rhythms and thereby optimize energy utilization across the 24-h cycle. We show that rhythmic heme degradation, which generates the signaling molecule carbon monoxide (CO), is required for normal circadian rhythms as well as circadian metabolic outputs. CO suppresses circadian transcription by attenuating CLOCK BMAL1 binding to target promoters. Pharmacological inhibition or genetic depletion of CO-producing heme oxygenases abrogates normal daily cycles in mammalian cells and Drosophila. In mouse hepatocytes, suppression of CO production leads to a global upregulation of CLOCK BMAL1dependent circadian gene expression and dysregulated glucose metabolism. Together, our findings show that CO metabolism is an important link between the basic circadian-clock machinery, metabolism and behavior.