Role of Endothelial Regulation of Fatty Acid Uptake in Metabolic Dysfunction

摘要 糖尿病的心血管并发症仍然是卫生保健系统的巨大负担。所有 目前批准的抗糖尿病治疗，迄今为止只有一类已证明任何显着 改善心血管结局。新的治疗策略，可以结合改善 降低心血管并发症的血糖控制将代表着 我们如何管理这些具有挑战性的患者群体。为此，我们建议调查一部令人兴奋的小说， 靶向由G蛋白偶联受体APLNR驱动的基于内皮的信号级联的策略， 我们描述了其抗血糖和动脉粥样硬化保护作用的机制基础。一个关键的机械基础 对于这个策略，正如在这个提议中所概述的，是利用它作为代谢转运屏障的功能， 积极调节脂肪酸在靶器官如骨骼肌中的转运和摄取， 确定胰岛素敏感性和葡萄糖利用率。我们令人兴奋的初步数据，包括：1）演示 在有条件的内皮特异性Aplnr缺失小鼠中血糖控制的显著损害，2）发现 FOXO 1是一种重要的代谢转录因子，是爱帕琳的一个新的信号转导靶点，爱帕琳通过FOXO 1诱导其表达。 通过磷酸化和胞质易位失活，3）证明了 FOXO 1通过apelin在内皮中导致FABP 4（AP 2）表达的抑制，FABP 4（AP 2）表达调节反式- 内皮FA转运，和4）鉴定爱帕琳/APLNR和APLNR之间的新的基于内皮的串扰， 胰岛素/胰岛素受体（IR）信号传导。根据这些挑衅性的初步数据，我们将解决 假设内皮APLNR信号转导是内皮功能的重要调节因子， FA的摄取和运输。目的1将利用体内和体外方法来确定 爱帕琳-APLNR信号传导和胰岛素-IR信号传导之间的串扰。目标2将确定代谢的作用， 最近发现的第二个APLNR配体。目标3将推动 这些发现是通过测试新的APLNR激动剂在实验性糖尿病中的功效和机制基础来实现的。 和动脉粥样硬化模型。总的来说，我们的研究将大大扩展我们对一种新的内皮细胞的认识， 基于信令范式，调节能源利用，在上下文中有多种含义， 糖尿病及其相关的心血管并发症的全球流行。

Abstract Cardiovascular complications of diabetes continue to remain a huge burden on the health care system. Of all the currently approved anti-diabetic therapies, only one class to date has demonstrated any significant improvement in cardiovascular outcomes. Novel therapeutic strategies that can couple improvements in glycemic control with reduction of cardiovascular complications would represent a significant advancement in how we manage these challenging patient population. To this end, we propose to investigate an exciting novel strategy to target the endothelial based signaling cascade driven by the G protein coupled receptor APLNR, as we characterize the mechanistic basis of its anti-glycemic and atheroprotective effects. A key mechanistic basis for this strategy, as outlined in this proposal, is to exploit its function as the metabolic transport barrier that actively regulates the transport and uptake of fatty acid in target organs such as skeletal muscles, which in turn determines insulin sensitivity and glucose utilization. Our exciting preliminary data, including: : 1) demonstration of marked impairment of glycemic control in conditional, endothelial specific Aplnr deleted mice, 2) discovery of FOXO1, a key metabolic transcription factor, as a novel signaling target of apelin, whereby apelin induces its inactivation via phosphorylation and cytoplasmic translocation, 3) demonstration that the negative regulation of FOXO1 by apelin in the endothelium leads to suppression of FABP4 (AP2) expression, which regulates trans- endothelial FA transport, and 4) identification of novel endothelial based crosstalk between apelin/APLNR and insulin/insulin receptor (IR) signaling. Based on these provocative preliminary data, we will address the hypothesis that endothelial APLNR signaling is an essential regulator of the endothelial function as a gatekeeper of FA uptake and transport. Aim 1 will utilize in vivo and in vitro approaches to determine the mechanism of crosstalk between apelin-APLNR signaling and insulin-IR signaling. Aim 2 will determine the metabolic role of elabela, the recently identified second APLNR ligand. Aim 3 will push forward the translational application of these findings by testing the efficacy and mechanistic basis of novel APLNR agonists in experimental diabetes and atherosclerosis models. Overall, our studies will significantly expand our knowledge of a novel endothelial- based signaling paradigm that regulates energy resource utilization, with multiple implications in the context of the worldwide epidemic of diabetes and its associated cardiovascular complications.