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一个巨大负担。最重要的是 目前批准的抗糖尿病疗法，到目前为止只有一类显示出显著的 改善心血管结果。新的治疗策略可以结合改善 随着心血管并发症的减少，血糖控制将是在 我们如何管理这些具有挑战性的患者群体。为此，我们建议研究一部激动人心的小说 靶向G蛋白偶联受体APLNR、AS驱动的内皮信号级联反应的策略 我们描述了其降血糖和动脉粥样硬化保护作用的机制基础。一个关键的机制基础 对于这一战略，正如本提案中概述的那样，是利用其作为代谢运输屏障的功能，即 积极调节靶器官如骨骼肌中脂肪酸的运输和摄取，进而 确定胰岛素敏感性和葡萄糖利用率。我们令人振奋的初步数据，包括：1)演示 在条件性、内皮特异性AplnR缺失的小鼠中发现显著的血糖控制障碍，2)发现 Foxo1，一个关键的代谢转录因子，作为apelin的一个新的信号靶点，由此apelin诱导其 通过磷酸化和细胞质易位失活，3)表明负调控 Foxo1通过内皮apelin抑制FABP4(AP2)的表达，FABP4(AP2)调节血管内皮细胞的反式-磷脂酰肌醇-1的表达。 内皮FA转运，以及4)鉴定APELIN/APLNR和APLNR之间基于内皮的新的串扰 胰岛素/胰岛素受体(IR)信号传导。基于这些具有挑衅性的初步数据，我们将解决 内皮细胞APLNR信号是内皮细胞把关功能的重要调节因子的假说 对FA的吸收和转运。目的1将利用体内和体外方法来确定其作用机制 APELIN-APLNR信号和INS-IR信号之间的串扰。目标2将确定其代谢作用 ELABELA，最近发现的第二个APLNR配体。目标3将推动翻译应用 通过测试新型APLNR激动剂对实验性糖尿病的疗效和机制基础，这些发现 和动脉粥样硬化模型。总体而言，我们的研究将极大地扩展我们对一种新型内皮细胞的知识- 基于控制能源利用的信号模式，在以下背景下具有多重含义 糖尿病及其相关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.