Regulation of Gene Expression by Dietary Fat

膳食脂肪对基因表达的调节

• 批准号: 7578716
• 负责人: LISA M SALATI
• 金额: $ 34.18万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7578716
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Alternative Splicing; Arachidonic Acids; Atherosclerosis; Binding; Calories; Cancerous; Cell Nucleus; Cells; Cholesterol; Chronic Disease; Data; Development; Diabetes Mellitus; Diet; Dietary Fats; Eating; Elements; Enhancers; Enzymes; Eukaryota; Event; Exons; Fatty Acids; Fatty acid glycerol esters; Gene Expression; Gene Expression Regulation; Genes; Glucosephosphate Dehydrogenase; Goals; Hepatocyte; Hormonal; Hormones; Insulin; Insulin Resistance; Intake; Introns; Link; Literature; Liver; Metabolism; Modeling; Molecular; Mutate; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Protein; Nuclear Proteins; Nucleic Acid Regulatory Sequences; Nutrient; Nutritional status; Obesity; Pathway interactions; Phosphatidylinositols; Phosphorylation; Phosphorylation Site; Phosphotransferases; Polyunsaturated Fatty Acids; Post-Translational Protein Processing; Process; Protein Family; Protein Splicing; Proteins; Public Health; RNA; RNA Sequences; RNA Splicing; RNA-Binding Proteins; Rattus; Recommendation; Recruitment Activity; Regulation; Regulatory Element; Risk Factors; Role; Serum; Signal Transduction; Signal Transduction Pathway; Spliceosome Assembly Pathway; Starvation; Testing; Tissues; Trans-Activators; Transcript; Transcriptional Regulation; Triglycerides; atypical protein kinase C; cell transformation; cell type; enhancer binding protein; gain of function; genetic regulatory protein; genome sequencing; growth hormone regulating factor; inositol 3-phosphate; loss of function; mitogen-activated protein kinase p38; polyunsaturated fat; prevent; prototype; public health relevance; research study; response

DESCRIPTION (provided by applicant): The amount and type of fat in the diet has been the subject of public health recommendations to prevent obesity, diabetes and atherosclerosis. A considerable body of literature has developed that suggests that eating the majority of calories as fat results in the development of insulin resistance and type II diabetes mellitus. Much less is known about how non-pathological fluctuations in dietary fat intake alter intracellular metabolism and how these signaling actions affect events in the nucleus. In the course of our studies on mechanisms by which fatty acids regulate gene expression, we discovered that the rate of RNA splicing is inhibited in liver and primary hepatocytes by dietary polyunsaturated fat and by arachidonic acid, respectively. Using the glucose-6-phosphate dehydrogenase (G6PD) enzyme, which lacks transcriptional regulation, as a unique model we have generated a prototype for extending these findings to other genes. Because greater than 60% of genes undergo alternative splicing and many are also regulated by changes in splicing efficiency, these findings will have widespread signficance for determining the proteins expressed within cells throughout development and in muliple cell types. The central hypothesis of this application is that genes that under regulated splicing comtain splicing regulatory regions in an exon. These regions contain juxtaposed splicing silencing and enhancing elements. The binding of splicing inhibitory proteins to the silencer exclude the binding of splicing activators proteins to the enhancer. Polyunsaturated fatty acids regulate the activity of the splicing regulatory proteins by posttranslational modification and/or nuclear abundance. The splicing regulatory region of exon 12 of the G6PD gene is our paradigm for these studies. Despite the ubiquitous need for regulated splicing, little is known about the intracellular signals regulating this process. In the course of these studies, we will define intracellular signal transduction pathways by which nutrients and nutritional status can alter the activity or abundance of splicing regulatory proteins. Thus, the experiments in the current proposal will provide new data on regulation of splicing pre se and define a new pathway by which nutrients regulate gene expression. PUBLIC HEALTH RELEVANCE: The amount and type of fat in the diet has been the subject of public health recommendations to prevent obesity, diabetes and atherosclerosis. A considerable body of literature has developed that suggests that eating the majority of calories as fat results in the development of insulin resistance and type II diabetes mellitus. In addition, the amount and type of fat in the diet can regulate the levels of serum cholesterol and triglycerides, risk factors for atherosclerosis. This project will provide important new data on the ways in which dietary fat can regulate intracellular metabolism.

说明(申请人提供)：饮食中脂肪的数量和类型一直是预防肥胖、糖尿病和动脉粥样硬化的公共卫生建议的主题。大量文献表明，将大部分卡路里作为脂肪摄入会导致胰岛素抵抗和II型糖尿病的发生。关于饮食脂肪摄入量的非病理性波动如何改变细胞内新陈代谢，以及这些信号活动如何影响细胞核内的事件，我们知道的要少得多。在我们对脂肪酸调控基因表达机制的研究过程中，我们发现饲料中的多不饱和脂肪和花生四烯酸分别抑制了肝脏和原代肝细胞中RNA的剪接速度。使用缺乏转录调节的葡萄糖-6-磷酸脱氢酶(G6PD)酶作为一个独特的模型，我们已经生成了一个原型，将这些发现扩展到其他基因。由于超过60%的基因经历了选择性剪接，而且许多基因还受到剪接效率变化的调控，这些发现将对确定细胞发育过程中和多种细胞类型中表达的蛋白质具有广泛的意义。这一应用的中心假设是，在受调控剪接下的基因包含外显子中的剪接调控区域。这些区域包含并列的剪接、沉默和增强元件。剪接抑制蛋白与沉默蛋白的结合排除了剪接激活蛋白与增强子的结合。多不饱和脂肪酸通过翻译后修饰和/或核丰度来调节剪接调节蛋白的活性。G6PD基因第12外显子的剪接调节区是我们进行这些研究的范例。尽管调控剪接的需求无处不在，但人们对调控这一过程的细胞内信号知之甚少。在这些研究过程中，我们将确定细胞内信号转导途径，通过这些途径，营养和营养状态可以改变剪接调节蛋白的活性或丰度。因此，本方案中的实验将为剪接压力的调控提供新的数据，并定义一条营养物质调控基因表达的新途径。与公共健康相关：饮食中脂肪的数量和类型一直是预防肥胖、糖尿病和动脉粥样硬化的公共健康建议的主题。大量文献表明，将大部分卡路里作为脂肪摄入会导致胰岛素抵抗和II型糖尿病的发生。此外，饮食中脂肪的数量和类型可以调节血清胆固醇和甘油三酯的水平，这两个因素是动脉粥样硬化的危险因素。该项目将为膳食脂肪调节细胞内代谢的方式提供重要的新数据。