2,3,7,8-Tetrachlorodibenzo-p-dioxin abolishes circadian regulation of hepatic metabolic activity in mice
2,3,7,8-Tetrachlorodibenzo-p-dioxin abolishes circadian regulation of hepatic metabolic activity in mice
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DOI：
10.1038/s41598-019-42760-3
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发表时间：
2019-04-24
影响因子：
4.6
通讯作者：
Zacharewski, Timothy R.
中科院分区：
文献类型：
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作者：
Fader, Kelly A.;Nault, Rance;Zacharewski, Timothy R.
据报道，芳烃受体（AhR）的激活可以改变肝脏生物钟调节因子的表达，但对生物钟控制代谢的影响尚未得到深入研究。本研究检测了AhR激活对雄性C57BL/6小鼠肝脏转录组和代谢组节律的影响，每4天口服2,3,7,8-四氯二苯并-对二恶英（TCDD） 28天。TCDD以剂量依赖的方式降低了几个核心时钟调节因子（如Arntl， clock, Nr1d1, Per1, Cry1, Nfil3）的节律性，包括>= 3.3倍的振幅抑制或振荡完全丧失。因此，在治疗后，选定调节因子的蛋白质水平（ARNTL, REV-ERBa, NFIL3）和基因组结合（ARNTL）降低并出现不规律。结果，5636个时钟控制的肝脏基因中99.6%的振荡表达被消除，包括与脂质代谢、葡萄糖/糖原和血红素相关的基因。例如，TCDD使糖异生（Pck1）和糖生成（Gys2）中限速酶的表达变平，这与肝糖原水平的消耗和节律性丧失相一致。通过非靶向质谱法检测极性肝脏提取物显示，几乎所有振荡代谢物在治疗后都失去了节律性。总之，这些结果表明TCDD破坏了肝脏代谢的昼夜节律调节，改变了代谢效率和能量储存。
Aryl hydrocarbon receptor (AhR) activation is reported to alter the hepatic expression of circadian clock regulators, however the impact on clock-controlled metabolism has not been thoroughly investigated. This study examines the effects of AhR activation on hepatic transcriptome and metabolome rhythmicity in male C57BL/6 mice orally gavaged with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) every 4 days for 28 days. TCDD diminished the rhythmicity of several core clock regulators (e.g. Arntl, Clock, Nr1d1, Per1, Cry1, Nfil3) in a dose-dependent manner, involving either a >= 3.3-fold suppression in amplitude or complete loss of oscillation. Accordingly, protein levels (ARNTL, REV-ERBa, NFIL3) and genomic binding (ARNTL) of select regulators were reduced and arrhythmic following treatment. As a result, the oscillating expression of 99.6% of 5,636 clock-controlled hepatic genes was abolished including genes associated with the metabolism of lipids, glucose/glycogen, and heme. For example, TCDD flattened expression of the rate-limiting enzymes in both gluconeogenesis (Pck1) and glycogenesis (Gys2), consistent with the depletion and loss of rhythmicity in hepatic glycogen levels. Examination of polar hepatic extracts by untargeted mass spectrometry revealed that virtually all oscillating metabolites lost rhythmicity following treatment. Collectively, these results suggest TCDD disrupted circadian regulation of hepatic metabolism, altering metabolic efficiency and energy storage.