The mechanistic role of metabolic gene MTCH2/mtch-1 in lipid homeostasis, longevity, and fertility

代谢基因 MTCH2/mtch-1 在脂质稳态、长寿和生育能力中的机制作用

• 批准号: 10179267
• 负责人: ANDERS M NAAR
• 金额: $ 33.94万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10179267
• 关键词: Acetyl-CoA C-Acetyltransferase; Adult; Affect; Animal Model; Animals; Apoptosis; Binding; Biochemical; Biological Models; Body Weight; Caenorhabditis elegans; Calories; Cardiovascular system; Caring; Cell Culture Techniques; Cell Maintenance; Cell Nucleus; Cells; Centers for Disease Control and Prevention (U.S.); Co-Immunoprecipitations; Coenzyme A; Cultured Cells; Data; Development; Diet; Drug or chemical Tissue Distribution; ESR1 gene; Enoyl-CoA Hydratase; Environmental Risk Factor; Enzymes; Epidemic; Family; Fatty Acids; Fatty acid glycerol esters; Fertility; Financial Hardship; Food; General Population; Genes; Genetic; Genetic Epistasis; Heart Diseases; Height; Homeostasis; Hormone Receptor; Human; Individual; Infertility; Inflammation; Insulin; Intestines; Knock-out; Lead; Life; Link; Lipids; Longevity; Malignant Neoplasms; Mammals; Mass Spectrum Analysis; Mediating; Medical; Metabolic; Methods; Mitochondria; Modeling; Molecular; Mus; Muscle; Mutagenesis; Mutate; Mutation; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Envelope; Nuclear Hormone Receptors; Obesity; Obesity associated disease; Outer Mitochondrial Membrane; Pathway interactions; Phenotype; Physiological; Play; Point Mutation; Predisposition; Prevalence; Process; Proteins; Public Health; Regulation; Reporting; Reproduction; Role; Signal Transduction; Signaling Molecule; Site; Skin; Stearoyl-CoA Desaturase; Sterility; System; Techniques; Testing; Thinness; Tissues; cancer type; comorbidity; dietary restriction; dosage; experimental study; gene environment interaction; genome wide association study; germline stem cells; insight; knock-down; lipid metabolism; member; metabolic phenotype; mutant; obese person; overexpression; overweight adults; response; sedentary lifestyle; synergism

Over 70% of US adults are overweight and over one-third are obese. This causes an alarming increase in the prevalence of obesity co-morbidities, such as type II diabetes, heart diseases, and certain types of cancer. Many environmental factors, such as a sedentary lifestyle and high calorie diets contribute to this epidemic; however, the predisposition of individuals to develop obesity under these conditions has a strong genetic component. Numerous Genome-Wide Association Studies have found significant associations between specific genes, obesity, and obesity associated diseases. By understanding gene-environment interactions that lead to obesity, it will be easier to develop approaches and therapies to reduce obesity levels and/or associated co-morbidities, which will increase the general public health and reduce financial burden associated with extra medical care. In this application, we propose in depth studies of the mechanism of action of MTCH2 (mitochondrial carrier 2), one of the strongest obesity-associated genes. In our preliminary studies in several model systems (cells, worms, and mice), we discovered that activating this gene is sufficient to induce obesity, while knocking down this gene significantly reduces adiposity indicating that MTCH2 is both required and sufficient for lipid accumulation. In addition to energy storage, fatty acids and their derivatives can serve as signaling molecules. Since MTCH2 influences fatty acid processing enzymes, it is possible that composition of lipids and therefore their signaling functions change, which might be the reason for some of the MTCH2 phenotypes. We will investigate this possibility by assessing the composition of lipids using biochemical and mass spectrometry approaches in cultured cells and animals with MTCH2 mutated or overexpressed. In addition to regulation of fat content, we showed that this gene influences fertility and longevity; however, the mechanisms by which MTCH2 regulates all three processes remain elusive. MTCH2 was found to be residing mainly on the outer mitochondrial membrane, and our preliminary data suggest that it interacts and could affect estrogen receptor 1 (ESR1) function. We hypothesize that MTCH2 might sequester hormone receptors to the mitochondria to alter mitochondrial function, or to be part of mitochondria-ER-nuclear membrane contact sites. It is possible that these MTCH2 functions are responsible for the observed metabolic phenotypes. We will use in depth localization, co-localization, and interaction studies in cells, worms, and mice to investigate where MTCH2 is located (intracellularly and tissue distribution), what other proteins it binds to, and which tissues are critical for MTCH2 regulation of adiposity, fertility and longevity. Finally, we will use C. elegans genetics (sterility suppressor screen and analysis of available point mutations) to discover the pathways and specific genes that mediate MTCH2 impact on lipid homeostasis, fertility, and lifespan.

超过70%的美国成年人超重，超过三分之一的人肥胖。这导致肥胖合并症（如II型糖尿病、心脏病和某些类型的癌症）患病率的惊人增长。许多环境因素，如久坐不动的生活方式和高热量饮食都是造成这种流行病的原因；然而，在这些条件下，个体发展为肥胖的倾向有很强的遗传成分。许多全基因组关联研究发现，特定基因、肥胖和肥胖相关疾病之间存在显著关联。通过了解导致肥胖的基因-环境相互作用，将更容易开发出减少肥胖水平和/或相关合并症的方法和治疗方法，这将提高公众健康水平，减少与额外医疗护理相关的经济负担。在这项应用中，我们建议深入研究MTCH2（线粒体载体2）的作用机制，MTCH2是最强的肥胖相关基因之一。在我们对几种模型系统（细胞、蠕虫和小鼠）的初步研究中，我们发现激活该基因足以诱导肥胖，而敲除该基因可显著减少肥胖，这表明MTCH2对于脂质积累既是必需的，也是充分的。除了储存能量外，脂肪酸及其衍生物还可以作为信号分子。由于MTCH2影响脂肪酸加工酶，因此脂质组成及其信号功能可能发生改变，这可能是某些MTCH2表型的原因。我们将通过使用生化和质谱方法评估MTCH2突变或过表达的培养细胞和动物的脂质组成来研究这种可能性。除了调节脂肪含量外，我们还发现该基因影响生育能力和寿命；然而，MTCH2调控这三个过程的机制仍然难以捉摸。我们发现MTCH2主要位于线粒体外膜，我们的初步数据表明它可以相互作用并影响雌激素受体1 （ESR1）的功能。我们假设MTCH2可能将激素受体隔离到线粒体以改变线粒体功能，或者是线粒体- er核膜接触点的一部分。这些MTCH2功能可能是观察到的代谢表型的原因。我们将在细胞、蠕虫和小鼠中进行深度定位、共定位和相互作用研究，以研究MTCH2的位置（细胞内和组织分布）、它结合的其他蛋白质以及哪些组织对MTCH2调节肥胖、生育和寿命至关重要。最后，我们将使用秀丽隐杆线虫遗传学（不育抑制筛选和可用点突变分析）来发现介导MTCH2对脂质稳态、生育和寿命影响的途径和特定基因。