Novel Post-Transcriptional Regulators of Lipid Metabolism

摘要 代谢综合征是一系列疾病，可以包括心脏病、肥胖症、糖尿病、肥胖症、糖尿病和糖尿病。 肝病和血脂异常。胆汁酸是胆固醇的代谢产物，可影响关键途径 参与维持代谢疾病中失调通路的稳态。胆汁酸是 这两种去污剂有助于脂质吸收，信号分子激活核受体FXR。一 目前正在临床上评估许多靶向FXR的药物。的成功 作为治疗剂的FXR激动剂需要深入了解由以下因素调节的分子途径： FXR，其中许多仍然未知。在这里，我们确定了一种新的机制，即FXR调节基因， 通过转录后机制表达。我们鉴定了一个FXR调节的RNA结合蛋白家族 （RBP）靶向特定mRNA并且在代谢中重要。更具体地说，我们表明，这些 RBP调节胆汁酸的合成和代谢。在具体目标1中，我们将确定 每种RBP的功能将改变小鼠中胆汁酸的体内平衡。使用体外方法，我们 将决定这种机制是否在人类环境中保守。在具体目标2中，我们将使用我们的 组织特异性敲除小鼠模型，以确定这些RNA结合蛋白的功能丧失是否 单独或组合导致胆汁酸合成和代谢的异常调节。我们 初步数据表明，肝脏中RBP家族成员之一的缺失会导致胆汁中的缺陷， 酸代谢我们还将确定这些RBP在肝脏中的分子靶点。我们的研究 将挑战目前关于胆汁酸代谢是如何被调节的范式，并确定一种新的 FXR被认为是如何维持胆汁酸稳态的分子机制。

ABSTRACT Metabolic syndrome is a constellation of diseases that can encompass heart disease, obesity, diabetes, fatty liver disease and dyslipidemia. Bile acids are metabolites of cholesterol that can affect critical pathways involved in maintaining homeostasis in pathways that are dysregulated in metabolic disease. Bile acids are both detergents that help lipid absorption and signaling molecules that activate the nuclear receptor FXR. A number of current pharmacologic agents targeting FXR are currently being evaluated clinically. The success of FXR agonists as therapeutic agents requires a deep understanding of the molecular pathways regulated by FXR, many of which remain unknown. Here, we identify a novel mechanism whereby FXR regulates gene expression via a post-transcriptional mechanism. We identify a family of FXR-regulated RNA binding proteins (RBPs) that target specific mRNAs and are important in metabolism. More specifically, we show that these RBPs regulate bile acid synthesis and metabolism. In Specific Aim 1, we will determine whether gain of function of each the RBPs will alter bile acid homeostasis in mice. Using a complimentary in vitro approach, we will determine whether this mechanism is conserved in a human context. In Specific Aim 2, we will use our tissue-specific knockout mouse models to determine whether loss of function of these RNA binding proteins either alone or in combination results in abnormal regulation of bile acid synthesis and metabolism. Our preliminary data demonstrate that loss of one of the RBP family members in the liver causes a defect in bile acid metabolism. We will also determine the molecular targets of these RBPs in the liver. Together, our studies will challenge the current paradigm for how bile acid metabolism is thought to be regulated, and identify a novel molecular mechanism for how FXR is thought to maintain bile acid homeostasis.