Intestinal epithelial cells-derived exosomal miRNAs regulate liver inflammation in obesity

该项目的主要主题是探索肥胖导致肝脏炎症/损伤的机制。 我们将重点研究肠上皮细胞(IECS)和巨噬细胞的细胞外miRNAs。具体来说，我们将 研究多不饱和脂肪酸介导的肠道炎症如何刺激 来自IECS的胞外miRNAs以及这些事件的后果。新的体外和体内研究方法 将用于处理行动机制，目的是确定新的干预目标。我们 提出膳食n-6多不饱和脂肪酸(n-6 PUFAs)促进肝脏炎症和损伤 通过IEC衍生的外切体。我们特别提出，STAT3激活的胞外miRNAs是关键 对肥胖小鼠肝脏巨噬细胞积聚/极化的影响。基于我们已发表的工作和 其他初步数据，这一提议将检验n-6多不饱和脂肪酸调节 细胞外的miRNAs通过STAT3信号从肠上皮细胞中释放出来，这在 肝内巨噬细胞、NK细胞和肝细胞。此外，我们将确定饮食中的脂肪是否与 携带miR-155抑制剂的纳米颗粒对肥胖具有潜在的治疗意义。这些假设 将在以下具体目标中进行测试：目标1：确定IEC来源的细胞外miRNAs 受n-6PUFAs/STAT3通路调控的是NFALD发生和发展的特异性介质 进步。目的2：确定通过STAT3调制改变IEC miRNAs是否影响 肥胖者高脂饲料所致肝脏炎症和损伤的严重程度。继成功完成 在上述特定目标上，我们的新研究将(I)验证STAT3激活的胞外miRNAs与 肥胖时肝巨噬细胞的蓄积/极化，以及(Ii)为未来的研究提供基础 肥胖治疗中饮食脂肪和细胞外miRNA调节的机制研究。

The overarching theme of this project is to explore the mechanisms that lead to liver inflammation/injury in obesity. We will focus on extracellular miRNAs of intestinal epithelial cells (IECs) and macrophages. Specifically, we will examine how polyunsaturated fatty acids mediated-intestinal inflammation stimulates the production of extracellular miRNAs from IECs and the consequences of these events. Novel in vitro and in vivo approaches will be used to address mechanisms of action with the goal of identifying new targets for intervention. We propose that dietary n-6 polyunsaturated fatty acids (n-6 PUFAs) promote liver inflammation and injury via IEC-derived exosomes. We specifically propose that Stat3-activated extracellular miRNAs are the key to the accumulation/polarization of macrophages in liver in obese mice. Based on our published work and other preliminary data, this proposal will test the hypothesis that the n-6 PUFAs regulate the production of extracellular miRNAs from intestinal epithelial cells through Stat3 signaling, which initiates a crosstalk among macrophages, NK cells and hepatocytes in liver. Moreover, we will determine whether diet fat-associated nanoparticles carrying miR-155 inhibitor have potential therapeutic implications in obesity. These hypotheses will be tested in the following Specific Aims: Aim 1: Determine whether IEC-derived extracellular miRNAs regulated by the n-6 PUFAs/Stat3 pathway are specific mediators of NFALD development and progression. Aim 2: Determine whether alteration of IEC miRNAs via STAT3 modulation affects the severity of HFD-induced liver inflammation and injury in obesity. Following the successful completion of the above Specific Aims, our novel studies will (i) validate Stat3-activated extracellular miRNAs is directly relevant to the accumulation/polarization of hepatic macrophages in obesity, and (ii) provide a foundation for future mechanistic investigation of the regulation of diet fat and extracellular miRNA in obesity therapy.