Bile acid composition and insulin sensitivity

项目摘要 胆汁酸组成对代谢调节有重要作用。胆汁酸的一个特殊亚类， 碳12中的羟基化位置（12 π）受胰岛素信号传导负调控， 在胰岛素抵抗的人群中合成率更高。12岁以下的人表现出改善， 葡萄糖和脂质代谢，但这些影响的机制是未知的。长期以来， 在理解胆汁酸组成调节全身代谢的机制方面取得了进展， 缺乏一个与实验相关的小鼠模型。但令人振奋的最新进展揭示了 人源化胆汁酸组合物的小鼠模型。在这项资助中，我们将使用人源化小鼠来解剖 胆汁酸组成，特别是12-β调节脂质的生理和分子机制 葡萄糖代谢我们将研究在肝脏，肠道和脂肪组织，三个关键的影响。 12个碱基可能发挥其差异效应的组织。我们将补充金标准在体内小鼠 用离体和体外系统进行研究以分离胆汁酸组合物的细胞自主效应。 这项工作的成功将揭示胆汁酸组成调节代谢的基本机制 体内平衡，并可能告知药理学尝试，特别是减少代谢疾病的12 β 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.