Novel Post-Transcriptional Regulators of Lipid Metabolism

摘要 代谢综合征是一系列疾病，包括心脏病、肥胖、糖尿病、肥胖症 肝病和血脂异常。胆汁酸是胆固醇的代谢物，可以影响关键途径。 参与在代谢性疾病中调节失调的通路中维持动态平衡。胆汁酸是 既有帮助脂肪吸收的洗涤剂，也有激活核受体FXR的信号分子。一个 目前以FXR为靶点的一些药理药物目前正在进行临床评估。的成功之处 作为治疗药物的FXR激动剂需要深入了解 FXR，其中许多仍然未知。在这里，我们确定了FXR调节基因的一种新机制 通过转录后机制表达。我们鉴定了一类受FXR调节的RNA结合蛋白 (限制性商业惯例)以特定的mRNAs为靶标，在新陈代谢中起重要作用。更具体地说，我们展示了这些 限制性商业惯例调节胆汁酸的合成和代谢。在具体目标1中，我们将确定是否获得 每种限制性商业惯例的作用都会改变小鼠的胆汁酸稳态。使用免费的体外方法，我们 将决定这一机制在人类环境中是否保守。在具体目标2中，我们将使用我们的 组织特异性基因敲除小鼠模型确定这些RNA结合蛋白功能是否丧失 无论单独或联合应用，都会导致胆汁酸合成和代谢的异常调节。我们的 初步数据显示，肝脏中RBP家族成员之一的缺失会导致胆汁缺陷。 酸代谢。我们还将确定这些限制性商业惯例在肝脏中的分子靶点。共同努力，我们的研究 将挑战目前被认为是如何调节胆汁酸代谢的范式，并发现了一种新的 FXR被认为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.