Bile acids and insulin sensitivity

项目摘要 胆汁酸（BA）信号通路是代谢性疾病的新的治疗靶点。一个潜在 方法是改善内源性BA的组成。人类有几十种BA， 每一个都不同地能够执行BA功能。我们以前已经确定了一个子集的BA-那些 在碳12位含有羟基-由肝脏胰岛素信号调节，增加 在人类胰岛素抵抗中，并与代谢功能障碍相关。通过以下方法消除12-羟基BA 切除合成它们所需的酶Cyp 8b 1，可以降低体重、血脂和葡萄糖。然而 这些改进的分子机制尚不完全清楚，特别是 从而导致改进的可编程性。因此，我们已经确定了三个基本的，未回答的问题，为我们的 研究：首先，需要哪些信号通路来实现这些改善？第二， 12-羟基苯甲酸对细胞代谢和信号级联的直接影响？三、代谢有哪些 在既存糖尿病/肥胖症中消除12-羟基BA的益处？这些问题将在 体内和离体，使用遗传、生物化学和人源化工具。建议的研究将改善我们的 了解这种保守的酶在生理学和其作为一种新的治疗策略的潜力。

PROJECT SUMMARY Bile acid (BA) signaling pathways are plausible new therapeutic targets for metabolic disease. One potential approach is to improve the composition of endogenous BAs. Humans have dozens of species of BAs, and each is differently able to carry out BA functions. We have previously identified a subset of BAs–those containing a hydroxyl group at the carbon 12 position–that are regulated by hepatic insulin signaling, increased in human insulin resistance, and correlated with metabolic dysfunctions. Eliminating 12-hydroxy BAs by ablating the enzyme required for their synthesis, Cyp8b1, lowers body weight, lipids, and glucose. However the molecular mechanisms of these improvements are incompletely understood, particularly the mechanisms leading to improved glycemia. Thus we have identified three fundamental, unanswered questions for our studies: First, what signaling pathways are required to bring about these improvements? Second, what are the direct effects of 12-hydroxy BAs on cellular metabolic and signaling cascades? Third, what are the metabolic benefits of eliminating 12-hydroxy BAs in pre-existing diabetes/obesity? These questions will be addressed in vivo and ex vivo, using genetic, biochemical, and humanized tools. The proposed studies will improve our understanding of this conserved enzyme in physiology and its potential as a new therapeutic strategy.