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Discovery and characterization of a novel acylcarnitine transporter in brown adipocytes

棕色脂肪细胞中新型酰基肉碱转运蛋白的发现和表征

基本信息

批准号：
10681400
负责人：
Judith Anne Simcox
金额：
$ 31.1万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681400
关键词：
Address Adipocytes Adipose tissue Adult Affect American Biological Assay Biological Markers Blood Brown Fat CRISPR library CRISPR screen Cardiovascular Diseases Cardiovascular system Carrier Proteins Cell Culture Techniques Cell membrane Cell physiology Cells Cessation of life ChIP-seq Development Diabetes Mellitus Disease Energy Metabolism Gene Expression Genomics Glucose Health Heart Homeostasis In Vitro Individual Insulin Resistance Knock-out Knowledge Link Lipids Liver Luciferases Mass Spectrum Analysis Mediating Membrane Transport Proteins Metabolic Metabolic Diseases Metabolism Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity associated disease Overweight PPAR gamma Pathway interactions Pharmacological Treatment Physiologic Thermoregulation Physiological Plasma Population Primary carcinoma of the liver cells Process Production Regulation Reporter Respiration Signal Transduction Skeletal Muscle Source Supercritical Fluid Chromatography Thermogenesis Time Tissue Sample Tissues Transcript United States Work acylcarnitine aged blood glucose regulation chromatin immunoprecipitation experimental study fatty acid oxidation glucose tolerance glucose uptake improved in vivo in vivo Model insight insulin regulation insulin sensitivity insulin signaling insulin tolerance mouse model novel obesity treatment overexpression prevent promoter protein expression resistance mechanism response solute targeted treatment theories therapeutic target tissue/cell culture uptake

项目摘要

Project Summary/Abstract In the United States, 42% of the population is obese, and this obesity predisposes individuals for several diseases including type 2 diabetes which affects 29 million Americans. One established mechanism for the causal relationship between obesity and type 2 diabetes is the development of lipotoxicity, a state where excess lipids build-up to cause increased ectopic lipid droplets, elevated plasma lipids, and subsequently, decreased cellular insulin signaling. These plasma lipids that are increased with lipotoxicity include acylcarnitines, a key intermediate in fatty acid oxidation. Acylcarnitines are an established biomarker of type 2 diabetes, hepatocellular carcinoma, and cardiovascular disease, and are known to cause insulin resistance. Despite the known importance of plasma acylcarnitines in the development of insulin resistance, we do not know how they are imported into cells, how this uptake is regulated, or how imported acylcarnitines are metabolized once they enter the cell from the circulatory system. In this proposal we examine the regulation of acylcarnitine uptake by transporters we have identified through a CRISPR/Cas9 screen. Through targeted knockout of these transporters, we will conduct cell culture experiments to highlight the precise molecular pathways through which acylcarnitines enter the cell and signal for insulin sensitivity. We will also explore tissue specific loss of acylcarnitines in mouse models to determine the contribution of plasma acylcarnitine uptake on whole-body energy expenditure, glucose regulation, and plasma lipid pools. Finally, we will determine how these transporters for plasma acylcarnitines are regulated in cell culture and tissue samples from mice to establish potential therapeutic targets for the treatment of metabolic disease. The proposed work will address long-standing questions on the molecular regulation of plasma acylcarnitine import, metabolism of acylcarnitines after entry into the cell, and the regulation of insulin sensitivity by acylcarnitines. In terms of translatability, this work will generate a mechanistic understanding of how plasma acylcarnitine abundance is controlled and how plasma acylcarnitines impact disease vulnerability to enable the identification of new targets for the pharmacological treatment of obesity and diabetes.

项目总结/摘要在美国，42%的人口肥胖，这种肥胖倾向于个人的几个包括影响2900万美国人的2型糖尿病在内的疾病。一个既定机制，肥胖和2型糖尿病之间的因果关系是脂毒性的发展，脂质积聚导致异位脂滴增加，血浆脂质升高，随后，细胞胰岛素信号传导。这些随着脂毒性而增加的血浆脂质包括酰基肉毒碱，这是一个关键脂肪酸氧化中间体。酰基肉毒碱是2型糖尿病、肝细胞癌和糖尿病的既定生物标志物。癌症和心血管疾病，并且已知引起胰岛素抵抗。尽管已知血浆酰基肉毒碱在胰岛素抵抗的发展中的重要性，我们不知道它们是如何输入到细胞中，这种摄取是如何调节的，或者一旦进入细胞，输入的酰基肉毒碱如何代谢。循环系统中的细胞。在这项建议中，我们研究了酰基肉毒碱摄取的转运蛋白，我们已经确定，通过一个 CRISPR/Cas9筛选。通过靶向敲除这些转运蛋白，我们将进行细胞培养实验强调酰基肉毒碱进入细胞并发出胰岛素信号的精确分子途径灵敏度我们还将探索小鼠模型中酰基肉毒碱的组织特异性损失，以确定血浆酰基肉毒碱摄取对全身能量消耗、血糖调节和血浆脂质池。最后，我们将确定这些血浆酰基肉毒碱转运蛋白在细胞内是如何被调节的，小鼠的培养物和组织样本，以建立治疗代谢性疾病的潜在治疗靶点疾病拟议的工作将解决长期存在的问题上的分子调节血浆酰基肉碱输入，进入细胞后酰基肉毒碱的代谢，以及胰岛素敏感性的调节，酰基肉毒碱就可翻译性而言，这项工作将对等离子体如何产生机械的理解控制酰基肉毒碱丰度以及血浆酰基肉毒碱如何影响疾病易感性，用于肥胖症和糖尿病的药理学治疗的新靶点的鉴定。