Novel effectors of insulin action in the liver

肝脏中胰岛素作用的新型效应器

基本信息

批准号：
9886405
负责人：
Fajun James Yang
金额：
$ 53.34万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-03 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886405
关键词：
ADD-1 protein Acute Adipose tissue American Animal Model Attenuated Binding Biochemical Cardiovascular Diseases Chronic Chronic Disease Complex DNA Binding Data Development Diabetes Mellitus Diabetic mouse Diagnosis Diet Energy Metabolism Enzymes Epidemic Eukaryotic Cell Exclusion Fasting Fatty Liver GATA4 gene Gene Delivery Gene Expression Genes Genetic Genetic Transcription Genetic Variation Genetic study Gluconeogenesis Goals Health Health Care Costs Hepatic Hepatocyte Hormonal Hormones Human Genetics Hyperglycemia Hypertriglyceridemia Insulin Insulin Resistance Intervention Link Lipids Liver MED15 Mammalian Cell Mediator of activation protein Metabolic Metabolic Diseases Metabolism Molecular Molecular Analysis Mus Mutation Names Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Receptors Nutritional Obesity Obesity Epidemic Outcome Study Pathogenesis Pathology Phenotype Phosphoenolpyruvate Carboxylase Prevalence Prevention strategy Preventive Protein Subunits RNA Polymerase II Reagent Regulation Reporting Rodent Model Role Signal Transduction Techniques Testing Tissues Transcriptional Regulation United States Work base blood glucose regulation cofactor diabetic endoplasmic reticulum stress enzyme activity gain of function glucose metabolism glucose production hepatic gluconeogenesis human model insight insulin regulation insulin signaling lipid biosynthesis lipid metabolism metabolic abnormality assessment mouse model novel novel strategies overexpression public health relevance transcription factor

项目摘要

Project Summary/Abstract: Type 2 diabetes is an epidemic health problem, but in part due to the incomplete understanding on the underlying mechanisms, the current treatments or preventive options are limited. A central paradox in the pathogenesis of type 2 diabetes is the selective mode of hepatic insulin resistance, in which insulin fails to suppress hepatic gluconeogenesis but continues to stimulate lipogenesis, resulting in hyperglycemia and hypertriglyceridemia. Although the acute regulation of glucose and lipid metabolism is largely through changes in metabolite flux and allosteric modulation of key enzyme activities, the chronic regulation of metabolism requires gene transcription. As a cofactor that links multiple transcription factors to RNA polymerase II, the Mediator complex has merged as an important regulator of metabolism. The mammalian Mediator complex is composed of up to 30 subunits. Our central hypothesis is that the Mediator complex integrates hormonal and/or nutritional signals with metabolic gene expression by connecting relevant transcription factors to RNA polymerase II through specific binding domains within particular Mediator subunits. This proposal is focused on a novel interaction between the Mediator subunit MED15 and GATA4 transcription factor. In addition to our previous work showing that MED15 stimulates lipogenesis by co- activating SREBP-1c transcription factor, our preliminary studies support a role of hepatic GATA4/MED15 complex in activating gluconeogenesis and in the development of insulin resistance. Interestingly, although the molecular mechanisms are unknown, human genetic studies indicate that mutations in Gata4 gene (likely gain of function) among all reported genetic variations display the strongest correlation with hypertriglyceridemia. Our hypothesis will be tested in two Specific Aims: Aim 1 will study insulin regulation of hepatic GATA4 in glucose metabolism, and Aim 2 will study the role of hepatic MED15 coactivating SREBP-1c and GATA4 in insulin resistance. A combined genetic and gene delivery approaches together with metabolic, biochemical and molecular analyses will be used to carry out these Aims. All key animal models, reagents and techniques have been established, and supportive preliminary results have been obtained. Overall, successful completion of the proposed studies will yield a novel insight into the mechanisms underlying selective hepatic insulin resistance, and may also aid the development of novel interventional strategies against type 2 diabetes.

项目摘要/摘要： 2 型糖尿病是一个流行的健康问题，但部分原因是人们对 2 型糖尿病的认识不完全。潜在的机制，目前的治疗或预防选择是有限的。一个中心悖论 2型糖尿病的发病机制是肝脏胰岛素抵抗的选择性模式，其中胰岛素不能发挥作用。抑制肝脏糖异生，但继续刺激脂肪生成，导致高血糖和高甘油三酯血症。虽然糖脂代谢的急性调节很大程度上是通过代谢物通量的变化和关键酶活性的变构调节，慢性调节新陈代谢需要基因转录。作为将多个转录因子与 RNA 连接的辅助因子聚合酶 II，介体复合物已合并成为代谢的重要调节剂。哺乳动物介体复合体由多达 30 个亚基组成。我们的中心假设是中介者复合物将激素和/或营养信号与代谢基因表达整合在一起通过特异性结合域将相关转录因子连接至RNA聚合酶II 在特定的介体亚单位内。该提案的重点是介导亚基 MED15 和 GATA4 之间的新颖相互作用转录因子。除了我们之前的工作表明，MED15 通过共同刺激脂肪生成激活 SREBP-1c 转录因子，我们的初步研究支持肝脏 GATA4/MED15 的作用激活糖异生和胰岛素抵抗发展的复合体。有趣的是，虽然分子机制尚不清楚，人类遗传学研究表明Gata4基因突变（可能的功能获得）在所有报告的遗传变异中显示出最强的相关性高甘油三酯血症。我们的假设将在两个具体目标中得到检验：目标 1 将研究胰岛素调节肝脏GATA4在葡萄糖代谢中的作用，目标2将研究肝脏MED15共激活的作用 SREBP-1c 和 GATA4 在胰岛素抵抗中的作用。结合遗传和基因传递方法代谢、生化和分子分析将用于实现这些目标。所有关键动物模型、试剂和技术已经建立，并取得了支持性的初步结果获得。总体而言，成功完成拟议的研究将对以下领域产生新的见解：选择性肝胰岛素抵抗的潜在机制，也可能有助于新型药物的开发针对 2 型糖尿病的干预策略。