Metabolite control of transcription

转录的代谢控制

• 批准号: 7732098
• 负责人: richard l veech
• 金额: $ 23.16万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7732098
• 关键词: Acetyl Coenzyme A; Acetylation; Alcohol consumption; Amino Acids; Area; Binding Proteins; Biochemistry; Biological; Caenorhabditis elegans; Caloric Restriction; Carbohydrates; Cells; Characteristics; Circadian Rhythms; Clinical; Condition; Development; Diapause; Diet; Dietary Carbohydrates; Disease; Drosophila genus; Enzymes; Fatty acid glycerol esters; Fertility; Genes; Genetic Transcription; Genome; Glucose; Glycolysis; Growth Factor; Hepatocyte; Hexoses; Histone H2B; Histones; Homeostasis; Institutes; Insulin; Insulin Resistance; Ketoses; Ketosis; Life; Lipids; Longevity; Mammals; Measures; Metabolic; Metabolic Control; Metabolic syndrome; Metabolism; Metformin; Methods; Muscle Cells; Myoblasts; NADP; National Institute on Alcohol Abuse and Alcoholism; Niacinamide; Nicotinamide adenine dinucleotide; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Numbers; Obesity; Organism; Oxidation-Reduction; Oxygen measurement, partial pressure, arterial; Pathway interactions; Personal Satisfaction; Phenotype; Physiological; Play; Property; Proteins; Publications; Reference Standards; Regulation; Resistance; Resveratrol; Role; Science; Signal Transduction; Sirolimus; Sterols; Stress; System; Textbooks; Thinking; United States National Institutes of Health; Vascular Diseases; Work; Xylulose; Yeasts; age related; alcohol effect; enzyme activity; heart function; interest; lipid biosynthesis; octamer transcription factor OTF-1; programs; pyridine nucleotide; red wine; senescence; transcription factor; Acetyl Coenzyme A; Acetylation; Alcohol consumption; Amino Acids; Area; Binding Proteins; Biochemistry; Biological; Caenorhabditis elegans; Caloric Restriction; Carbohydrates; Cells; Characteristics; Circadian Rhythms; Clinical; Condition; Development; Diapause; Diet; Dietary Carbohydrates; Disease; Drosophila genus; Enzymes; Fatty acid glycerol esters; Fertility; Genes; Genetic Transcription; Genome; Glucose; Glycolysis; Growth Factor; Hepatocyte; Hexoses; Histone H2B; Histones; Homeostasis; Institutes; Insulin; Insulin Resistance; Ketoses; Ketosis; Life; Lipids; Longevity; Mammals; Measures; Metabolic; Metabolic Control; Metabolic syndrome; Metabolism; Metformin; Methods; Muscle Cells; Myoblasts; NADP; National Institute on Alcohol Abuse and Alcoholism; Niacinamide; Nicotinamide adenine dinucleotide; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Numbers; Obesity; Organism; Oxidation-Reduction; Oxygen measurement, partial pressure, arterial; Pathway interactions; Personal Satisfaction; Phenotype; Physiological; Play; Property; Proteins; Publications; Reference Standards; Regulation; Resistance; Resveratrol; Role; Science; Signal Transduction; Sirolimus; Sterols; Stress; System; Textbooks; Thinking; United States National Institutes of Health; Vascular Diseases; Work; Xylulose; Yeasts; age related; alcohol effect; enzyme activity; heart function; interest; lipid biosynthesis; octamer transcription factor OTF-1; programs; pyridine nucleotide; red wine; senescence; transcription factor

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 coordinated control of ChREBP is exerted by the simple hexose monophosphate pathway metabolite, xylulose 5-P (Veech RL, PNAC 2003;100:5578-80). 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 2003;293:510-4) CtBP, the transcriptional co-repressor playing a role in development and transformation, (Fjeld C et al, PNAS 2003;100:9202-7) Oct-1, the transcription factor regulating expression of nuclear histones, H2B, (McKnight S, Cell 2003;114:150-2). 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 (Fulco M et al, Mol Cell 2003;12:51-62). 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 continuing 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. Reducing insulin/IGF signaling allows for organismal survival during periods of inhospitable conditions by regulating the diapause state, whereby the organism stockpiles lipids, reduces fertility, increases stress resistance, and has an increased lifespan. The Target of Rapamycin (TOR) responds to changes in growth factors, amino acids, oxygen tension, and energy status; however, it is unclear how TOR contributes to physiological homeostasis and disease conditions. Here, we show that reducing the function of Drosophila TOR results in decreased lipid stores and glucose levels. Importantly, this reduction of dTOR activity blocks the insulin resistance and metabolic syndrome phenotypes associated with increased activity of the insulin responsive transcription factor, dFOXO. Reduction in dTOR function also protects against age-dependent decline in heart function and increases longevity. Thus, the regulation of dTOR activity may be an ancient "systems biological" means of regulating metabolism and senescence, that has important evolutionary, physiological, and clinical implications. 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 Lehningers 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.

摘要：越来越清楚，基因组中许多编码的蛋白质的转录受到小型代谢产物的控制，其浓度取决于环境条件。因此，食用富含碳水化合物的饮食会导致编码形成前体乙酰基COA所需的主要糖酵解酶以及产生NADPH脂肪合成所需的NADPH所需的己糖单磷酸途径所需的基因。转录因子称为Chrebp，对饮食中的碳水化合物反应。结合SREBP的作用，Brown和Goldstein描述的固醇反应性结合蛋白以及对胰岛素的反应，这两个转录因子在肥胖症，II型糖尿病和血管疾病中至关重要。这种优雅的Chrebp控制控制由简单的单磷酸途径代谢物，木糖糖5-P（Veech RL，PNAC 2003; 100：5578-80）施加。 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，已知会因酒精摄入而深刻改变。现在已知许多转录因子由吡啶核苷酸的氧化还原状态控制。 These include: NPAS2, the so-called clock gene responsible for circadian rhythm (Rutter J et al, Science 2003;293:510-4) CtBP, the transcriptional co-repressor playing a role in development and transformation, (Fjeld C et al, PNAS 2003;100:9202-7) Oct-1, the transcription factor regulating expression of nuclear histones, H2B, (McKnight S, Cell 2003; 114：150-2）。 Sir2，Gene Silencer认为在酵母，秀丽隐杆线虫以及哺乳动物中的热量限制的生命中起着核心作用。 在最近的工作中，在与其他群体的合作中完成的工作中，我们表明，肌细胞中siR2的活性受自由胞质NAD+/NADH的变化控制（Fulco M等，Mol Cell，2003; 12：51-62）。 目前，人们认为该酶的活性受烟酰胺的抑制作用，其Ki超过150微摩尔。我们正在继续检查在不同饮食条件下SIRT1量的变化。现在尚不清楚控制与NAD+/NADH比率的变化如何相关。毋庸置疑，NAD+/NADH的变化都是酒精摄入和酮症的特征，因此有望改变上述转录因子的活性。 减少胰岛素/IGF信号传导可以通过调节滞育状态，从而在无法享用的疾病时期内生存，从而使生物体储存脂质，降低生育能力，增加压力抗性，并具有增加的寿命。雷帕霉素（TOR）的靶标对生长因子，氨基酸，氧张力和能量状态的变化做出了反应。但是，目前尚不清楚TOR如何促进生理稳态和疾病状况。在这里，我们表明，降低果蝇的功能会导致脂质储存和葡萄糖水平降低。重要的是，DTOR活性的这种降低会阻止与胰岛素反应性转录因子DFOXO的活性增加有关的胰岛素抵抗和代谢综合征表型。 DTOR功能的降低还可以防止心脏功能的年龄依赖性下降并增加寿命。因此，DTOR活性的调节可能是调节新陈代谢和衰老的古老“系统生物学”手段，具有重要的进化，生理和临床意义。 对该研究所计划的意义 肥胖和减少它的方法是NIH路线图的主要目标。理解饮食碳水化合物在肥胖起源中的作用的工作对于理解和纠正这一问题至关重要。我们在这一领域的出版物得到了很好的接待，现在是新的Lehningers生物化学教科书中对脂肪生成代谢控制的标准参考。另外，对SIR2活性的控制被认为是延长热量限制特性的关键步骤。因此，由于乙醇摄入而导致的NAD+/NADH比率变化的能力对NIAAA以及白藜芦醇的能力具有重要意义，白藜芦醇是红酒的黄素分量，它刺激了SIR2活性。