Metabolite control of transcription

总结：越来越清楚的是，基因组中编码的许多蛋白质的转录是由小的代谢物控制的，这些代谢物的浓度取决于环境条件。因此，消耗富含碳水化合物的饮食导致编码形成前体乙酰辅酶A所需的糖酵解的主要酶以及产生脂肪合成所需的NADPH的己糖单磷酸途径的酶的基因的转录。这种转录因子被称为ChREBP，对饮食中的碳水化合物有反应。结合SREBP（由Brown和Goldstein描述的固醇响应性结合蛋白）的作用以及对胰岛素的响应，这两种转录因子在肥胖症、II型糖尿病和血管疾病中具有重要意义。ChREBP的这种优雅的协调控制由简单的己糖单磷酸途径代谢物木酮糖5-P发挥作用[1]。吡啶核苷酸的氧化还原状态的变化是代谢状态变化的标志，并且已知通过酒精摄入而深刻改变。现在已知许多转录因子受吡啶核苷酸的氧化还原状态控制。其中包括：NPAS 2，所谓的负责昼夜节律的时钟基因（Rutter，J.等，Science 293：510-514，2003）。等，PNAS 100：9202-9207，2003）Oct-1，调节核组蛋白表达的转录因子，H2 B，（McKnight，S. Cell 114：150-152，2003）。Sir 2基因沉默子被认为在酵母热量限制的生命延长特性中起核心作用，C. elegans线虫，and in mammals哺乳动物as well.在最近的工作中，我们与NIH等其他小组合作完成，我们已经表明成肌细胞中SIR 2的活性受游离胞质[NAD+]/[NADH]的变化控制[2]。目前认为，这种酶的活性是由烟酰胺的抑制作用控制的，Ki超过150微摩尔。我们正在继续研究不同饮食条件下Sirt 1含量的变化。目前尚不清楚控制如何与[NAD+]/[NADH]比率的变化相关。不言而喻，[NAD+]/[NADH]的变化是酒精摄入和酮症的特征，因此预计会改变上述转录因子的活性。 对本研究所方案的意义 肥胖和减少肥胖的方法是NIH路线图的主要目标。了解膳食碳水化合物在肥胖发生中的作用对于理解和纠正这个问题具有重要意义。我们在这一领域的出版物已被广泛接受，现在是标准的参考代谢控制脂肪生成的新莱宁格？的生物化学教科书。此外，Sir 2活性的控制被认为是热量限制延长寿命特性的关键步骤。因此，由乙醇摄入引起的[NAD+]/[NADH]比率变化的能力对NIAAA以及白藜芦醇（红葡萄酒的类黄酮成分）的能力具有重要意义，白藜芦醇刺激Sir 2活性。

Summary: It is becoming increasingly clear that transcription of many of the proteins encoded in the genome is controlled by small metabolites whose concentrations vary depending upon environmental conditions. Thus consuming a diet rich in carbohydrate leads to the transcription of the genes encoding the major enzymes of glycolysis required to form the precursor acetyl CoA as well as the enzymes of the hexose monophosphate pathway producing the NADPH required for fat synthesis. The transcription factor is called ChREBP and responds to dietary carbohydrate. Combined with the effects of SREBP, the sterol responsive binding protein described by Brown and Goldstein, and responsive to insulin, these two transcription factors are of major importance in obesity, type II diabetes and vascular diseases. This elegant co-ordinate control of ChREBP is exerted by the simple hexose monophosphate pathway metabolite, xylulose 5-P [1]. Changes in the redox state of the pyridine nucleotides are the hallmark of changes in metabolic status and is known to be profoundly altered by alcohol ingestion. A number of transcription factors are now known to be controlled by the redox state of the pyridine nucleotides. These include: NPAS2, the so-called clock gene responsible for circadian rhythm (Rutter, J. et al, Science 293: 510-514, 2003) CtBP, the transcriptional co-repressor playing a role in development and transformation, (Fjeld, C. et al, PNAS 100: 9202-9207, 2003) Oct-1, the transcription factor regulating expression of nuclear histones, H2B, (McKnight, S. Cell 114:150-152, 2003). Sir2, the gene silencer thought to play a central role in the life extending properties of caloric restriction in yeast, C. elegans, and in mammals as well. In recent work, done in colaboration with other groups as NIH, we have shown that the activity of SIR2 in myoblasts is controlled by changes in the free cytosolic [NAD+]/[NADH] [2]. Currently it is thought that the activity of this enzyme is controlled by inhibition by nicotinamide with a Ki of over 150 micromolar. We are contining the examination of changes induced in the amount of Sirt1 present in different dietary conditions . It is not now clear how control is related to change in the [NAD+]/[NADH] ratio. It goes without saying that changes in [NAD+]/[NADH] are characteristic of both alcohol ingestion and ketosis and would therefore be expected to alter the activity of the above listed transcription factors. SIGNIFICANCE TO THE PROGRAMS OF THIS INSTITUTE Obesity and methods to reduce it, is a major target of the NIH roadmap. Work in understanding the role of dietary carbohydrate in the genesis of obesity is of importance in understanding and correcting this problem. Our publication in this area has been well received and is now the standard reference on the metabolic control of lipogenesis in the new Lehninger?s textbook of biochemistry. In addition, the control of Sir2 activity is considered to be a key step in the life extending properties of caloric restriction. The ability of a changing [NAD+]/[NADH] ratio, which results from ethanol ingestion, is therefore of major significance to the NIAAA as well as the ability of resveratrol, a flavinoid component of red wine, which stimulates Sir2 activity.