Yin Lei, Wu Nan, Curtin Joshua C, Qatanani Mohammed, Szwergold Nava R, Reid Robert A, Waitt Gregory M, Parks Derek J, Pearce Kenneth H, Wisely G Bruce, Lazar Mitchell A
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Science. 2007 Dec 14;318(5857):1786-9. doi: 10.1126/science.1150179. Epub 2007 Nov 15.
The circadian clock temporally coordinates metabolic homeostasis in mammals. Central to this is heme, an iron-containing porphyrin that serves as prosthetic group for enzymes involved in oxidative metabolism as well as transcription factors that regulate circadian rhythmicity. The circadian factor that integrates this dual function of heme is not known. We show that heme binds reversibly to the orphan nuclear receptor Rev-erbalpha, a critical negative component of the circadian core clock, and regulates its interaction with a nuclear receptor corepressor complex. Furthermore, heme suppresses hepatic gluconeogenic gene expression and glucose output through Rev-erbalpha-mediated gene repression. Thus, Rev-erbalpha serves as a heme sensor that coordinates the cellular clock, glucose homeostasis, and energy metabolism.
昼夜节律钟在时间上协调哺乳动物的代谢稳态。其中的核心是血红素，一种含铁的卟啉，它作为参与氧化代谢的酶以及调节昼夜节律的转录因子的辅基。整合血红素这一双重功能的昼夜节律因子尚不清楚。我们发现，血红素与孤儿核受体Rev-erbalpha可逆性结合，Rev-erbalpha是昼夜节律核心时钟的一个关键负性成分，并调节其与核受体共抑制复合物的相互作用。此外，血红素通过Rev-erbalpha介导的基因抑制作用抑制肝脏糖异生基因的表达和葡萄糖输出。因此，Rev-erbalpha作为一种血红素传感器，协调细胞时钟、葡萄糖稳态和能量代谢。
