Exercise induced regulation of CYP7a1 and bile acid metabolism

项目总结/摘要 我的长期职业目标是成为一个成功的，独立的科学家与研究计划 集中在运动的综合生理反应，以确定潜在的治疗目标， 治疗和/或预防代谢疾病。肝脏脂肪变性，即肝脏中脂肪的过度储存， 成为全球慢性肝病最常见的原因。运动可以治疗和/或预防脂肪变性 与体重状态无关;然而，机制尚不清楚。在啮齿类动物中， 胆固醇7 α-羟化酶（CYP 7a 1）是胆汁酸（BA）合成的限速酶， 饮食诱导的脂肪变性和慢性运动产生类似的表型。CYP 7a 1受多种因素的调节 在餐后和空腹条件下的机制。在餐后条件下，诱导 CYP 7a 1和随后的BA合成通过叉头盒转录的胰岛素特异性失活而增加 因子1（FoxO 1）;而在空腹条件下，CYP 7a 1转录受细胞核定位的调控， 转录因子EB（TFEB）。重要的是，运动增强和/或恢复肝脏胰岛素作用， 增加TFEB在骨骼肌中的核定位。然而，它仍然是未知的， 通过这些机制提高和/或改善BA合成。我的总体假设是， 部分通过增强CYP 7a 1的转录调节，防止饮食诱导的肝脂肪变性 允许增加BA合成和粪便BA排泄，这使得肝脏乙酰辅酶A远离从头开始 脂肪生成在慢性营养过剩期间充当能量虹吸管（即，肥胖症）。我将全面测试这一点 在饮食诱导的肥胖小鼠中，通过研究运动对BA代谢的影响来验证这一假设。在目标1中，我将 确定急性运动诱导的肝胰岛素作用增强是否会增加餐后胰岛素水平 诱导CYP 7a 1转录和随后的BA合成。在目标2中，我将研究核武器是否 TFEB的易位和TFEB诱导的CYP 7a 1转录在CYP 7a 1的长期效应中起关键作用。 运动以上调肝脏BA代谢，并将过量的乙酰辅酶A从从头脂肪生成转移， 促进BA的合成和排泄。这些研究将有助于确定 运动通过一种新的途径防止肝脏脂肪变性，同时也为预防肝脏脂肪变性提供了良好的基础。 肝脏和综合代谢的训练。

PROJECT SUMMARY/ABSTRACT My long-term professional goal is to become a successful, independent scientist with a research program focused on the integrative physiological response of exercise to identify potential therapeutic targets for the treatment and/or prevention of metabolic disease. Hepatic steatosis, the excessive storage of fat in the liver, has become the most common cause of chronic liver disease worldwide. Exercise can treat and/or prevent steatosis independent of weight status; however, mechanisms remain unclear. In rodents, genetic overexpression of cholesterol 7 α-hydroxylase (CYP7a1), the rate limiting enzyme for bile acid (BA) synthesis, protects against diet-induced steatosis and chronic exercise produces a similar phenotype. CYP7a1 is regulated by numerous mechanisms during both postprandial, and fasting conditions. During postprandial conditions, induction of CYP7a1 and subsequent BA synthesis increases via insulin-specific inactivation of forkhead box transcription factor 1 (FoxO1); whereas under fasting conditions, CYP7a1 transcription is regulated by nuclear localization of transcription factor EB (TFEB). Importantly, exercise enhances and/or restores hepatic insulin action and increases nuclear localization of TFEB in skeletal muscle. However, it remains unknown if exercise contributes to elevated and/or improved BA synthesis through these mechanisms. My overall hypothesis is that exercise protects against diet-induced hepatic steatosis, in part, through enhanced transcriptional regulation of CYP7a1 allowing for increased BA synthesis and fecal BA excretion, which pulls hepatic acetyl-CoA away from de novo lipogenesis to act as an energetic siphon during chronic nutrient excess (i.e., obesity). I will test this overall hypothesis by investigating the impact of exercise on BA metabolism, in diet-induced obese mice. In Aim 1, I will determine whether enhanced hepatic-insulin action induced by acute exercise will increase postprandial induction of CYP7a1 transcription and subsequent BA synthesis. In Aim 2, I will investigate if nuclear translocation of TFEB and TFEB induced transcription of CYP7a1 plays a critical role in the long term effects of exercise to upregulate hepatic BA metabolism and divert excess acetyl-CoA away from de novo lipogenesis and toward BA synthesis and excretion. These studies will contribute to the identification of mechanisms by which exercise protects against hepatic steatosis through a novel pathway while also providing an excellent foundation of training in liver and integrative metabolism.