Bile acid composition and insulin sensitivity

胆汁酸组成和胰岛素敏感性

基本信息

批准号：
10752931
负责人：
Rebecca Anne Haeusler
金额：
$ 65.66万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752931
关键词：
Acids Adipocytes Adipose tissue Adult Affect Bile Acids Biological Models CYP8B1 gene Cannulations Carbon Cell Separation Cells Chylomicrons Closure by clamp Complement Data Diet Disease Enterocytes Enzymes Family Fatty Acids Fatty Liver Fructose GPBAR1 gene Genetic Glucose Clamp Grant Health High Fat Diet Homeostasis Human Hydroxylation Hyperinsulinism In Vitro Individual Infusion procedures Insulin Insulin Resistance Intestinal Absorption Intestines Knock-out Lipids Lipolysis Liver Lymph Measures Mediator Mesentery Metabolic Metabolic Diseases Metabolism Methods Molecular Mus Nonesterified Fatty Acids Pathogenesis Persons Physiological Physiology Play Positioning Attribute Process Production Property Regulation Research Signal Transduction Site System Tissues Tracer Very low density lipoprotein Work absorption blood glucose regulation blood lipid cell type extracellular fatty acid oxidation glucose metabolism humanized mouse improved in vivo insulin sensitivity insulin signaling lipid biosynthesis lipid metabolism liver metabolism mouse model muricholic acid pharmacologic receptor response success tool uptake

项目摘要

PROJECT SUMMARY Bile acid composition contributes strongly to metabolic regulation. The particular subset of bile acids that are hydroxylated in the carbon 12? position (12HBAs) are negatively regulated by insulin signaling and synthesized at higher rates in people with insulin resistance. People with low 12HBAs show improvements in glucose and lipid metabolism, but the mechanisms of these effects are unknown. A longstanding barrier to progress in understanding the mechanisms by which bile acid composition regulates systemic metabolism has been the lack of a translationally relevant mouse model. But exciting recent progress in the field has uncovered mouse models with humanized bile acid composition. In this grant, we will use humanized mice to dissect the physiologic and molecular mechanisms by which bile acid composition, particularly 12HBAs, regulate lipid and glucose metabolism. We will examine effects in the liver, the intestine, and the adipose tissue, three key tissues where 12HBAs may carry out their differential effects. We will complement gold-standard in vivo mouse studies with ex vivo and in vitro systems to isolate the cell autonomous effects of bile acid composition. Success of this work will reveal fundamental mechanisms by which bile acid composition regulates metabolic homeostasis and may inform pharmacologic attempts to specifically reduce 12HBAs for metabolic disease treatment.

项目概要胆汁酸成分对代谢调节有很大贡献。胆汁酸的特定子集是碳12上有羟基吗？位置 (12HBA) 受到胰岛素信号的负调节胰岛素抵抗患者的合成率较高。 12HBA 较低的人在以下方面表现出改善葡萄糖和脂质代谢，但这些影响的机制尚不清楚。长期存在的障碍在了解胆汁酸成分调节全身代谢的机制方面取得了进展缺乏翻译相关的小鼠模型。但该领域最近令人兴奋的进展已经被发现具有人源化胆汁酸成分的小鼠模型。在这笔资助中，我们将使用人源化小鼠来剖析胆汁酸成分（特别是 12HBA）调节脂质和代谢的生理和分子机制葡萄糖代谢。我们将检查对肝脏、肠道和脂肪组织这三个关键的影响 12HBA 可能发挥其不同作用的组织。我们将补充金标准体内小鼠利用离体和体外系统进行研究，以分离胆汁酸成分的细胞自主效应。这项工作的成功将揭示胆汁酸成分调节代谢的基本机制体内平衡，并可能为针对代谢疾病专门降低 12HBA 的药理学尝试提供信息治疗。