Tytgat Institute for Liver and Intestinal Research (formerly AMC Liver Center), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
J Biol Chem. 2011 May 6;286(18):16332-43. doi: 10.1074/jbc.M110.216986. Epub 2011 Mar 10.
Starvation elicits a complex adaptive response in an organism. No information on transcriptional regulation of metabolic adaptations is available. We, therefore, studied the gene expression profiles of brain, small intestine, kidney, liver, and skeletal muscle in mice that were subjected to 0-72 h of fasting. Functional-category enrichment, text mining, and network analyses were employed to scrutinize the overall adaptation, aiming to identify responsive pathways, processes, and networks, and their regulation. The observed transcriptomics response did not follow the accepted "carbohydrate-lipid-protein" succession of expenditure of energy substrates. Instead, these processes were activated simultaneously in different organs during the entire period. The most prominent changes occurred in lipid and steroid metabolism, especially in the liver and kidney. They were accompanied by suppression of the immune response and cell turnover, particularly in the small intestine, and by increased proteolysis in the muscle. The brain was extremely well protected from the sequels of starvation. 60% of the identified overconnected transcription factors were organ-specific, 6% were common for 4 organs, with nuclear receptors as protagonists, accounting for almost 40% of all transcriptional regulators during fasting. The common transcription factors were PPARα, HNF4α, GCRα, AR (androgen receptor), SREBP1 and -2, FOXOs, EGR1, c-JUN, c-MYC, SP1, YY1, and ETS1. Our data strongly suggest that the control of metabolism in four metabolically active organs is exerted by transcription factors that are activated by nutrient signals and serves, at least partly, to prevent irreversible brain damage.
饥饿会在生物体中引发复杂的适应性反应。目前尚无关于代谢适应转录调控的信息。因此，我们研究了经历 0-72 小时禁食的小鼠的大脑、小肠、肾脏、肝脏和骨骼肌的基因表达谱。我们采用功能类别富集、文本挖掘和网络分析来仔细研究整体适应情况，旨在确定响应途径、过程和网络及其调节。观察到的转录组反应并没有遵循公认的“碳水化合物-脂质-蛋白质”能量底物消耗的顺序。相反，在整个禁食期间，这些过程在不同的器官中同时被激活。最显著的变化发生在脂质和类固醇代谢中，特别是在肝脏和肾脏中。它们伴随着免疫反应和细胞更新的抑制，特别是在小肠中，以及肌肉中的蛋白质水解增加。大脑受到饥饿后遗症的严重保护。所鉴定的过度连接转录因子中，有 60%是器官特异性的，6%是 4 种器官共有的，核受体是主角，占禁食期间所有转录调节剂的近 40%。常见的转录因子有 PPARα、HNF4α、GCRα、AR（雄激素受体）、SREBP1 和 -2、FOXO、EGR1、c-JUN、c-MYC、SP1、YY1 和 ETS1。我们的数据强烈表明，四种代谢活跃器官的代谢控制是由营养信号激活的转录因子来发挥作用的，至少部分是为了防止不可逆的大脑损伤。
