Department of Cell and Developmental Biology, Life Sciences Institute, University of Michigan Medical Center, Ann Arbor, 48109, USA.
EMBO J. 2011 Sep 6;30(22):4642-51. doi: 10.1038/emboj.2011.322.
Temporal organization of tissue metabolism is important for maintaining nutrient and energy homeostasis in mammals. Autophagy is a conserved cellular pathway that is activated in response to nutrient limitation, resulting in the degradation of cytoplasmic components and the release of amino acids and other nutrients. Here, we show that autophagy exhibits robust circadian rhythm in mouse liver, which is accompanied by cyclic induction of genes involved in various steps of autophagy. Functional analyses of transcription factors and cofactors identified C/EBPβ as a potent activator of autophagy. C/EBPβ is rhythmically expressed in the liver and is regulated by both circadian and nutritional signals. In cultured primary hepatocytes, C/EBPβ stimulates the program of autophagy gene expression and is sufficient to activate autophagic protein degradation. Adenoviral-mediated RNAi knockdown of C/EBPβ in vivo abolishes diurnal autophagy rhythm in the liver. Further, circadian regulation of C/EBPβ and autophagy is disrupted in mice lacking a functional liver clock. We have thus identified C/EBPβ as a key factor that links autophagy to biological clock and maintains nutrient homeostasis throughout light/dark cycles.
组织代谢的时间组织对于维持哺乳动物的营养和能量稳态非常重要。自噬是一种保守的细胞途径，它会在营养物质限制时被激活，导致细胞质成分的降解和氨基酸和其他营养物质的释放。在这里，我们显示自噬在小鼠肝脏中表现出强烈的昼夜节律，伴随着参与自噬各个步骤的基因的周期性诱导。对转录因子和辅助因子的功能分析确定 C/EBPβ 是自噬的有效激活剂。C/EBPβ 在肝脏中呈节律性表达，受昼夜和营养信号的调节。在培养的原代肝细胞中，C/EBPβ 刺激自噬基因表达程序，足以激活自噬蛋白降解。体内腺病毒介导的 C/EBPβ RNAi 敲低可消除肝脏的昼夜自噬节律。此外，缺乏功能性肝脏时钟的小鼠中，C/EBPβ 和自噬的昼夜调节被打乱。因此，我们已经确定 C/EBPβ 是将自噬与生物钟联系起来并在光/暗周期内维持营养稳态的关键因素。
