Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate University of Chinese Academy of Sciences, Shanghai, China.
Hepatology. 2014 Jun;59(6):2196-206. doi: 10.1002/hep.26992. Epub 2014 Apr 25.
The protein deacetylase, sirtuin 1 (SIRT1), involved in regulating hepatic insulin sensitivity, shows circadian oscillation and regulates the circadian clock. Recent studies show that circadian misalignment leads to insulin resistance (IR); however, the underlying mechanisms are largely unknown. Here, we show that CLOCK and brain and muscle ARNT-like protein 1 (BMAL1), two core circadian transcription factors, are correlated with hepatic insulin sensitivity. Knockdown of CLOCK or BMAL1 induces hepatic IR, whereas their ectopic expression attenuates hepatic IR. Moreover, circadian change of insulin sensitivity is impaired in Clock mutant, liver-specific Bmal1 knockout (KO) or Sirt1 KO mice, and CLOCK and BMAL1 are required for hepatic circadian expression of SIRT1. Further studies show that CLOCK/BMAL1 binds to the SIRT1 promoter to enhance its expression and regulates hepatic insulin sensitivity by SIRT1. In addition, constant darkness-induced circadian misalignment in mice decreases hepatic BMAL1 and SIRT1 levels and induces IR, which can be dramatically reversed by resveratrol.
These findings offer new insights for coordination of the circadian clock and metabolism in hepatocytes by circadian regulation of hepatic insulin sensitivity via CLOCK/BMAL1-dependent SIRT1 expression and provide a potential application of resveratrol for combating circadian misalignment-induced metabolic disorders.
参与调节肝胰岛素敏感性的蛋白质去乙酰化酶，沉默调节蛋白 1（SIRT1），表现出昼夜节律性振荡并调节昼夜节律时钟。最近的研究表明，昼夜节律失调会导致胰岛素抵抗（IR）；然而，其潜在机制在很大程度上尚不清楚。在这里，我们表明，两个核心昼夜转录因子 CLOCK 和脑和肌肉 ARNT 样蛋白 1（BMAL1）与肝胰岛素敏感性相关。CLOCK 或 BMAL1 的敲低会诱导肝胰岛素抵抗，而它们的异位表达则会减弱肝胰岛素抵抗。此外，Clock 突变体、肝特异性 Bmal1 敲除（KO）或 Sirt1 KO 小鼠的胰岛素敏感性昼夜变化受损，并且 CLOCK 和 BMAL1 是肝 SIRT1 昼夜表达所必需的。进一步的研究表明，CLOCK/BMAL1 结合到 SIRT1 启动子上以增强其表达，并通过 SIRT1 调节肝胰岛素敏感性。此外，小鼠中持续黑暗诱导的昼夜节律失调会降低肝 BMAL1 和 SIRT1 水平并诱导 IR，而白藜芦醇可显著逆转这种情况。
这些发现为通过 CLOCK/BMAL1 依赖性 SIRT1 表达调节肝胰岛素敏感性来协调肝细胞中的昼夜节律时钟和代谢提供了新的见解，并为利用白藜芦醇对抗昼夜节律失调引起的代谢紊乱提供了一种潜在的应用。
