权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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/文摘