Interorgan Coordination of the Murine Adaptive Response to Fasting
Interorgan Coordination of the Murine Adaptive Response to Fasting
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DOI：
10.1074/jbc.m110.216986
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发表时间：
2011-05-06
影响因子：
4.8
通讯作者：
Sokolovic, Milka
中科院分区：
文献类型：
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作者：
Hakvoort, Theodorus B. M.;Moerland, Perry D.;Sokolovic, Milka
饥饿会在生物体中引起复杂的适应性反应。目前还没有关于代谢适应的转录调控的信息。因此，我们研究了禁食0-72小时的小鼠脑、小肠、肾脏、肝脏和骨骼肌的基因表达谱。功能范畴丰富、文本挖掘和网络分析被用来仔细审查总体适应，目的是确定反应路径、过程和网络及其调节。观察到的转录反应并不遵循公认的“碳水化合物-脂肪-蛋白质”能量底物消耗的顺序。相反，在整个过程中，这些过程在不同的器官中同时被激活。脂质和类固醇代谢变化最为显著，尤其是肝脏和肾脏。伴随而来的是免疫反应和细胞周转的抑制，特别是在小肠，并伴随着肌肉中蛋白质分解的增加。大脑在饥饿的后遗症中得到了极好的保护。在已鉴定的过度连接转录因子中，60%是器官特异性的，6%是4个器官共同的，以核受体为主角，占禁食期间所有转录调控因子的近40%。常见的转录因子有PPARα、HNF4α、GCRα、AR(雄激素受体)、SREBP1和-2、FOXOS、Egr1、c-jun、c-myc、SP1、YY1和ETS1。我们的数据有力地表明，四个代谢活跃器官的代谢控制是由转录因子施加的，这些转录因子由营养信号激活，至少部分地用于防止不可逆转的脑损伤。
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 PPAR alpha, HNF4 alpha, GCR alpha, 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.