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Them1-Mediated Metabolic Regulation and Pathogenic Role in NAFLD

Them1 介导的 NAFLD 代谢调节和致病作用

基本信息

批准号：
10836136
负责人：
DAVID E. COHEN
金额：
$ 69.72万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-05 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10836136
关键词：
3-Dimensional Acyl Coenzyme A Address Adipose tissue Binding Brown Fat Calories Catalysis Cell Nucleus Cell membrane Cells Consumption Cytoplasm Data Development Disease Electron Microscopy Energy Metabolism Enzymes Exhibits Fatty Acids Fatty Liver Fatty acid glycerol esters Gene Expression Genes Genetic Transcription Genetically Engineered Mouse Gluconeogenesis Glucose Goals Health Hepatic High Fat Diet Homeostasis Human Inflammation Insulin Resistance Lipid Binding Lipids Liver Mediating Medication Management Membrane Metabolic Metabolism Mission Mitochondria Molecular Mus Names National Institute of Diabetes and Digestive and Kidney Diseases Obesity Obesity associated liver disease Organelles Outcome Study Overnutrition Pathogenesis Pathogenicity Pathway interactions Phase Transition Play Process Public Health Regulation Research Research Proposals Rodent Role Temperature Testing Therapeutic Thermogenesis Transcriptional Regulation Triglycerides Up-Regulation Visualization biophysical techniques blood glucose regulation design diet-induced obesity endoplasmic reticulum stress expectation experimental study fatty acid oxidation feeding glucose production improved insight liver inflammation member new therapeutic target non-alcoholic fatty liver disease novel nutrient metabolism oxidation response small molecule small molecule inhibitor steroidogenic acute regulatory protein tissue culture trafficking

项目摘要

PROJECT SUMMARY/ABSTRACT Insulin resistance due to obesity is central to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). This research proposal addresses the unanswered question of how molecular mechanisms that normally promote energy conservation become maladaptive and contribute to NAFLD. The long-term goal of this research is to understand the regulatory relationships between cellular lipid molecules and metabolism, particularly as they present therapeutic opportunities. The objective of this research is to understand fundamental mechanisms for the regulation of energy homeostasis and nutrient metabolism. Our central hypothesis is that Them1 conserves energy by limiting thermogenesis in brown and beige adipose tissue through its functions both as a lipid-regulated enzyme that reduces rates of fatty acid oxidation and as a transcriptional coregulator. In obesity, we postulate that Them1 becomes maladaptive. In addition to limiting energy expenditure in thermogenic adipose tissue, high fat diet-induced Them1 upregulation in liver leads to steatosis and excess gluconeogenesis and in white adipose tissue to inflammation and insulin resistance. The rationale for the proposed research is that the mechanisms by which Them1 limits energy expenditure, while promoting hepatic steatosis and insulin resistance, will reveal specific new targets for the management of NAFLD. Guided by extensive preliminary data, the central hypothesis will be tested in three specific aims: 1) To define the maladaptive mechanisms whereby Them1 promotes obesity and NAFLD; 2) To determine the cellular mechanisms for suppression of thermogenesis by Them1; and 3) To elucidate regulation of Them1 activity by the lipid-binding START domain. In Aim 1, genetically engineered mice will be used to test the hypothesis that increased Them1 expression in white adipose tissue promotes inflammation, which leads to insulin resistance, hepatic inflammation and endoplasmic reticulum stress, and in beige adipose tissue reduces thermogenesis. Aim 2 will test the hypothesis that Them1 in brown adipose tissue organizes into membrane- less organelles (puncta) that conserve energy by suppressing fatty acid oxidation, except during peak energy demand, when Them1 is directed to the nucleus to support thermogenesis by suppressing lipogenic gene expression. We will visualize puncta by 3-D electron microscopy and elucidate the phase transition that promotes their formation, and will characterize Them1-mediated transcriptional regulation. Aim 3 will test the hypothesis that lipids bound to the START domain allosterically regulate the enzymatic domains. Our approach will include detailed structural analysis of Them1 lipid-binding and catalysis using complementary biophysical approaches, along with the development of small molecule inhibitors, which could also prove to be of therapeutic value in NAFLD. Overall, this proposal will elucidate Them1-mediated metabolic regulation, which is significant because mechanisms that conserve energy in health may promote disease under conditions of overnutrition. These studies are expected to identify therapeutic opportunities for the management of NAFLD.

项目总结/摘要肥胖引起的胰岛素抵抗是非酒精性脂肪性肝病（NAFLD）发病机制的核心。这项研究计划解决了一个悬而未决的问题，即通常情况下，促进节能变得适应不良，并有助于NAFLD。长期目标是研究是为了了解细胞脂质分子和代谢之间的调节关系，特别是因为它们提供了治疗机会。这项研究的目的是了解调节能量平衡和营养代谢的基本机制。我们的中央假设Them 1通过限制褐色和米色脂肪组织的产热来保存能量通过其作为一种降低脂肪酸氧化速率的脂质调节酶和作为一种转录辅助调节因子在肥胖症中，我们假设Them 1变得适应不良。除了限制产热脂肪组织的能量消耗，高脂饮食诱导的肝脏Them 1上调导致脂肪变性和过度增生，以及白色脂肪组织中的炎症和胰岛素抵抗。的拟议研究的基本原理是，主题1限制能量消耗的机制，而促进肝脂肪变性和胰岛素抵抗，将揭示具体的新目标， NAFLD。在广泛的初步数据的指导下，中心假设将在三个具体目标中进行测试：1）确定Them 1促进肥胖和NAFLD的适应不良机制; 2）确定Them 1促进NAFLD的机制。 Them 1抑制产热的细胞机制; 3）阐明Them 1的调控通过脂质结合START结构域的活性。在目标1中，基因工程小鼠将用于测试假设Them 1在白色脂肪组织中表达增加促进炎症，这导致胰岛素抵抗，肝脏炎症和内质网应激，并在米色脂肪组织减少产热作用目的2将检验棕色脂肪组织中Them 1组织成膜的假设- 通过抑制脂肪酸氧化来保存能量的细胞器（斑点）较少，峰值能量期间除外当Them 1被定向到细胞核以通过抑制脂肪生成基因来支持产热时，表情我们将通过三维电子显微镜观察斑点，并阐明相变，促进其形成，并将表征Them 1介导的转录调控。目标3将测试与START结构域结合脂质变构调节酶结构域的假设。我们的方法将包括Them 1脂质结合和催化的详细结构分析，使用互补生物物理方法，沿着小分子抑制剂的发展，这也可以证明是在NAFLD中的治疗价值总的来说，这项提议将阐明Them 1介导的代谢调节，意义重大，因为在健康状况下保存能量的机制可能会在以下条件下促进疾病营养过剩预计这些研究将确定NAFLD管理的治疗机会。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Flattening of circadian glucocorticoid oscillations drives acute hyperinsulinemia and adipocyte hypertrophy.

DOI：
10.1016/j.celrep.2022.111018
发表时间：
2022-06-28
期刊：
CELL REPORTS
影响因子：
8.8
作者：
Tholen, Stefan;Patel, Roma;Agas, Agnieszka;Kovary, Kyle M.;Rabiee, Atefeh;Nicholls, Hayley T.;Bielczyk-Maczynska, Ewa;Yang, Wenting;Kraemer, Fredric B.;Teruel, Mary N.
通讯作者：
Teruel, Mary N.

Mucosal defense: gastroduodenal injury and repair mechanisms.