Bile acid composition and insulin sensitivity

项目总结 胆汁酸的组成对代谢调节有很大的贡献。胆汁酸的特定子集是 在碳12中羟化了？位置(12HBA)受胰岛素信号和 在有胰岛素抵抗的人中合成的速度更快。12HBA低的人在以下方面表现出改善 糖和脂代谢，但这些作用的机制尚不清楚。一个长期存在的障碍 胆汁酸成分调节全身新陈代谢机制的研究进展 一直缺乏翻译上相关的老鼠模型。但该领域最新的令人兴奋的进展揭示了 小鼠模型中含有人源化胆汁酸成分。在这笔赠款中，我们将使用人源化的老鼠来解剖 胆汁酸成分，特别是12HBA，调节血脂和蛋白质的生理和分子机制 葡萄糖代谢。我们将检查对肝脏、肠道和脂肪组织的影响，这三个关键 12HBA可能发挥不同作用的组织。我们将补充体内小鼠的黄金标准 利用体外和体外系统分离胆汁酸成分的细胞自主效应的研究。 这项工作的成功将揭示胆汁酸组成调节代谢的基本机制 动态平衡，并可能为专门减少代谢疾病的12HBA的药物尝试提供信息 治疗。

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.