Exercise induced regulation of CYP7a1 and bile acid metabolism

项目摘要/摘要 我的长期职业目标是成为一名有研究计划的成功的独立科学家 重点关注运动的综合生理反应，以确定潜在的治疗靶点 治疗和/或预防代谢性疾病。肝脏脂肪变性，即脂肪在肝脏中的过度储存，对 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 与体重状况无关；然而，机制仍不清楚。在啮齿动物中，基因的过度表达 胆汁酸(BA)合成的限速酶--胆固醇7α羟基酶(CyP7a1)可防止胆汁酸的合成。 饮食引起的脂肪变性和慢性运动会产生类似的表型。CYP7a1受多种基因调控 在餐后和禁食条件下的作用机制。在餐后条件下，诱导 通过胰岛素特异性的叉头盒转录失活，CYP7a1和随后的BA合成增加 因子1(FoxO1)；而在禁食条件下，CYP7a1转录受细胞核定位调控。 转录因子EB(TFEB)。重要的是，运动增强和/或恢复肝脏胰岛素的作用 增加TFEB在骨骼肌中的核定位。然而，目前还不清楚锻炼是否会起作用。 通过这些机制促进和/或改善BA的合成。我的总体假设是锻炼 部分通过增强CYP7a1的转录调控来预防饮食诱导的肝脏脂肪变性 允许增加BA的合成和粪便BA的排泄，从而将肝脏的乙酰辅酶A从新生中拉出来 脂肪生成在慢性营养过剩(即肥胖)期间起到能量虹吸的作用。我要全面测试一下。 通过研究运动对饮食诱导肥胖小鼠BA代谢的影响提出假说。在《目标1》中，我将 确定急性运动引起的增强的肝脏胰岛素作用是否会增加餐后 诱导细胞色素P7a1转录和随后的BA合成。在目标2中，我将调查是否有核 TFEB易位及TFEB诱导的细胞色素P7a1转录在血管紧张素转换酶的长期效应中起关键作用 运动上调肝脏BA代谢，转移过剩的乙酰辅酶A，使其远离新生脂肪生成和 促进BA的合成和排泄。这些研究将有助于确定通过哪些机制 运动通过一种新的途径预防肝脏脂肪变性，同时也提供了良好的基础 肝脏训练和综合代谢。

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.