Mitochondrial BCAA transporter in physiology and disease

生理学和疾病中的线粒体支链氨基酸转运蛋白

• 批准号: 10318672
• 负责人: Shingo Kajimura
• 金额: $ 45.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318672
• 关键词: Adipocytes; Amino Acids; Animal Model; Animals; Biochemical; Branched-Chain Amino Acids; Brown Fat; Catabolic Process; Catabolism; Cell model; Cells; Code; Coupled; Cytosol; Data; Defect; Development; Diet; Disease; Emission-Computed Tomography; Energy Metabolism; Epidemiology; FRAP1 gene; Fatty Acids; Gatekeeping; Genes; Genetic Transcription; Glucose; Glucose Intolerance; Health; Homeostasis; Hormones; Human; Image; Impairment; Insulin Resistance; Isoleucine; Knock-in; Leucine; Lipids; Liposomes; Mammals; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Oxides; Phenotype; Physiological; Physiology; Positron-Emission Tomography; Regulation; Role; Scanning; Signal Pathway; Signal Transduction; System; Testing; Thermogenesis; Tissues; Transcriptional Regulation; Triglycerides; Valine; Variant; Weight Gain; Work; X-Ray Computed Tomography; base; blood glucose regulation; diabetic; disease phenotype; epidemiology study; glucose tolerance; improved; in vivo; innovation; insight; insulin sensitivity; insulin signaling; man; metabolic phenotype; metabolomics; novel; oxidation; stem; uptake

PROJECT SUMMARY Emerging evidence suggests that brown adipose tissue (BAT) functions as a significant metabolic-sink for glucose and fatty acids, but also branched-chain amino acids (BCAA; valine, leucine, and isoleucine). Our recent study shows that cold-activated BCAA catabolism in the BAT promotes systemic BCAA clearance in mice and humans, and that this metabolic-sink action is tightly coupled with its ability to improve glucose tolerance and insulin sensitivity. The notion of BAT being a metabolic-sink for BCAA provides new insights into the epidemiological observations that increased circulating BCAA levels are associated with insulin resistance and type 2 diabetes, conditions under which BAT mass/activity is reduced. However, the mechanisms remain insufficiently understood because the gatekeeper of mitochondrial BCAA transport, i.e., mitochondrial BCAA transporter that determines BCAA fate in the mitochondria vs. cytosol, was unknown for many years. We recently identified the first mitochondrial BCAA transporter, SLC25A44, in mammals. Our preliminary data suggest that SLC25A44 is required for mitochondria BCAA oxidation, BAT thermogenesis, and systemic glucose homeostasis. Accordingly, this proposal aims to determine the mechanisms by which SLC25A44 loss causes systemic glucose intolerance and insulin resistance. First, we will determine the metabolic organ that is primarily responsible for the diabetic phenotype through characterization of the newly developed BAT-specific SLC25A44 deficient mice. Second, we will employ metabolomics and biochemical approaches to determine the molecular mechanisms by which SLC25A44 loss alters mitochondrial function and intracellular signaling pathways. Lastly, we aim to examine the regulatory mechanisms of SLC25A44 expression and function. The work resulting from this application will establish a conceptual framework to understand the regulation of intracellular BCAA fate, and also provide a new roadmap to reverse disease phenotypes that stem from dysregulation in the BCAA catabolic processes.

项目摘要 新出现的证据表明，棕色脂肪组织（BAT）作为一个重要的代谢库， 葡萄糖和脂肪酸，还有支链氨基酸（BCAA;缬氨酸、亮氨酸和异亮氨酸）。我们最近 研究表明，BAT中的冷活化BCAA催化剂促进小鼠全身BCAA清除， 人类，并且这种代谢库作用与其改善葡萄糖耐量的能力紧密相关， 胰岛素敏感性 BAT是支链氨基酸代谢汇的概念为流行病学观察提供了新的见解 循环中支链氨基酸水平的增加与胰岛素抵抗和2型糖尿病有关， 在此情况下，BAT质量/活性降低。然而，这些机制仍然没有得到充分的理解， 线粒体BCAA转运的看门人，即，决定支链氨基酸的线粒体支链氨基酸转运蛋白 线粒体与细胞质中的命运，多年来一直是未知的。 我们最近在哺乳动物中发现了第一个线粒体BCAA转运蛋白SLC 25 A44。我们的初步数据 表明SLC 25 A44是线粒体BCAA氧化、BAT产热和全身葡萄糖所必需 体内平衡因此，本提案旨在确定SLC 25 A44缺失导致的机制。 全身性葡萄糖耐受不良和胰岛素抵抗。首先，我们将确定代谢器官， 通过表征新开发的BAT特异性SLC 25 A44负责糖尿病表型 缺陷小鼠其次，我们将采用代谢组学和生物化学方法来确定分子水平。 SLC 25 A44缺失改变线粒体功能和细胞内信号通路的机制。最后， 我们的目的是研究SLC 25 A44的表达和功能的调节机制。工作产生于 本申请将建立理解细胞内BCAA命运调节的概念框架， 并提供了一个新的路线图，以扭转疾病的表型，源于失调的支链氨基酸 分解代谢过程