Mechanisms in Metabolic Control in C. elegans.

线虫代谢控制机制。

• 批准号: 8664368
• 负责人: Amy Karol Walker
• 金额: $ 36.44万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664368
• 关键词: Acetyl Coenzyme A; Affect; Anabolism; Animals; Automobile Driving; Binding; Binding Proteins; Biogenesis; Biology; Caenorhabditis elegans; Carbon; Cardiovascular Diseases; Cell Culture System; Cell Culture Techniques; Cell physiology; Cells; Cholesterol; Cholesterol Homeostasis; Choline; Complex; DNA Modification Process; Defect; Development; Diet; Disease; Disease Progression; Eating; Elements; Ensure; Environmental Risk Factor; Enzymes; Epigenetic Process; Equilibrium; Fatty Acids; Fatty Liver; Feedback; Folate; Food; Functional disorder; Gene Activation; Gene Expression; Gene Silencing; Genes; Genetic Transcription; Genetic Variation; HMGB1 Protein; Hereditary Disease; Homeostasis; Homocysteine; Homocystine; Human; Invertebrates; Knowledge; Lecithin; Life; Link; Lipids; Liver diseases; Malignant neoplasm of liver; Mammalian Cell; Mammals; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Metabolism; Methionine; Methods; Methylation; Modeling; Modification; Molecular; Mus; NADP; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Protein; Orthologous Gene; Pathway interactions; Phenotype; Phosphatidylcholine Biosynthesis; Phospholipids; Physiological; Post-Translational Protein Processing; Process; Production; Protein Family; Proteins; RNA Interference; Reaction; Regulation; Regulator Genes; Regulatory Element; Research; SRE-1 binding protein; Signal Transduction; Sterols; System; Transcription Coactivator; Transcriptional Regulation; activating transcription factor; fatty acid biosynthesis; gene synthesis; human disease; in vivo; in vivo Model; lipid biosynthesis; lipid metabolism; methyl group; mutant; novel; nutrition; nutrition related genetics; promoter; protein activation; protein function; research study; therapy development; transcription factor

DESCRIPTION (provided by applicant): Life depends upon the conversion of food to energy. However, imbalances in food intake, genetic variations or environmental factors can alter metabolic pathways, causing type 2 diabetes, fatty liver disease, metabolic syndrome or cardiovascular disease. Determining causes and effects in such a complex system is difficult; therefore it is important to identify common regulatory points that may impact multiple metabolic endpoints. Transcription factors from the SREBP (sterol regulatory binding element protein) family coordinate activation of genes necessary for fatty acid, cholesterol and phospholipid biosynthesis (Horton, 2002). They also insure these biosynthetic pathways have adequate building blocks by expressing Acetyl CoA and NADPH synthesis genes. We have found that SREBPs are important for generating another metabolite linked to these processes: s-adenosyl methionine (SAMe). SAMe is produced by the one carbon cycle (1CC) and necessary for phospholipid biosynthesis and epigenetic modification in addition to other cellular processes. A growing body of evidence has linked 1CC function with fatty liver disease and the development of liver cancer (Mato, 2008). Our finding that SREBPs affect expression of key genes in this pathway suggests lipid homeostasis and levels of 1CC metabolites such as methionine, homocysteine, and SAMe may be coordinately regulated. In this proposal, we will combine studies in C. elegans, an invertebrate model with conserved lipid biology, with mechanistic analysis in mammalian cell culture systems to determine which aspects of 1CC are essential for SREBP function in vivo. We will examine if signals directing SREBP activation of fatty acid biosynthesis genes also affect 1CC genes. Phenotypic analysis of a SREBP target in the 1CC has revealed that sams-1 (s-adenosyl methionine syntase) knockdown causes formation of large lipid droplets. These droplets are reminiscent of the hepatic steatosis appearing when the mouse ortholog (MAT1A) is targeted (Mato, 2008) and suggest C. elegans may model aspects of the lipid accumulation in fatty liver disease. C. elegans are amenable to rapid gene inactivation by RNAi, metabolic profiling and dietary manipulation, providing an excellent model for dissecting the regulatory interactions between SREBP and 1CC metabolism which can be expanded in more complex mammalian models. The experiments in this proposal will impact our understating of links between nutrition, metabolism and disease.

描述（由申请人提供）：生命取决于食物向能量的转化。然而，食物摄入不平衡、遗传变异或环境因素可能会改变代谢途径，导致 2 型糖尿病、脂肪肝、代谢综合征或心血管疾病。确定如此复杂的系统中的原因和影响是很困难的。因此，确定可能影响多个代谢终点的共同监管点非常重要。 SREBP（甾醇调节结合元件蛋白）家族的转录因子协调脂肪酸、胆固醇和磷脂生物合成所需基因的激活（Horton，2002）。他们还通过表达乙酰辅酶A和NADPH合成基因来确保这些生物合成途径具有足够的构建模块。我们发现 SREBP 对于生成与这些过程相关的另一种代谢物非常重要：s-腺苷甲硫氨酸 (SAMe)。 SAMe 由单碳循环 (1CC) 产生，除了其他细胞过程外，它也是磷脂生物合成和表观遗传修饰所必需的。越来越多的证据表明 1CC 功能与脂肪肝疾病和肝癌的发展有关（Mato，2008）。我们发现 SREBP 影响该途径中关键基因的表达，这表明脂质稳态和 1CC 代谢物（如蛋氨酸、同型半胱氨酸和 SAMe）的水平可能受到协调调节。 在本提案中，我们将结合线虫（一种具有保守脂质生物学的无脊椎动物模型）的研究与哺乳动物细胞培养系统的机制分析，以确定 1CC 的哪些方面对于体内 SREBP 功能至关重要。我们将检查指导脂肪酸生物合成基因的 SREBP 激活的信号是否也影响 1CC 基因。对 1CC 中 SREBP 靶标的表型分析表明，sams-1（s-腺苷甲硫氨酸合酶）敲低会导致大脂滴的形成。这些液滴让人想起当小鼠直系同源物 (MAT1A) 被靶向时出现的肝脏脂肪变性 (Mato, 2008)，并表明秀丽隐杆线虫可能模拟脂肪肝疾病中脂质积累的各个方面。线虫能够通过 RNAi、代谢分析和饮食控制实现快速基因失活，为剖析 SREBP 和 1CC 代谢之间的调节相互作用提供了一个极好的模型，该模型可以在更复杂的哺乳动物模型中扩展。该提案中的实验将影响我们对营养、新陈代谢和疾病之间联系的理解。