CSN8 regulation of S1P-enriched extracellular vesicles to modulate NAFLD by gut-liver axis

这个项目的主要主题是解决肠道来源的细胞外小泡的潜在机制。 非酒精性脂肪性肝病(NAFLD)中(EVS)诱导的肝脏炎症/损伤。我们将确定角色 鞘磷脂代谢产物，具体地说；富含鞘氨醇1-磷酸(S1P)的肠道Evs和途径 CSN8/SphK1在NAFLD发生发展中的作用目前的提议将肠道来源的电动汽车与巨噬细胞联系起来- 通过提出肠道细胞外小泡将巨噬细胞招募到肝脏来介导炎症， 导致肝脏损伤和炎症。我们最近的工作已经开始识别由肠道炎症引起的 EVS的改变，并表明肠源性EVS在NKT细胞和Th17的调节中发挥关键作用 细胞通过肠-肝轴参与肝脏炎症和结肠癌的发展。我们的初步数据显示 内毒素促进肠上皮细胞释放富含鞘磷脂代谢产物的促炎作用 EVS包括神经酰胺和S1P。我们的初步发现也表明CSN8/SphK1信号通路 在生产富含S1P的电动汽车中起着至关重要的作用。长期摄入高脂肪饮食会导致增加 肠道通透性和肝脏暴露于肠道衍生产品，包括IECS的EVS。增加了S1P富集度 EVS激活其在肝巨噬细胞上的受体S1P1，可能促进巨噬细胞趋化进入 肝脏。这导致了一个中心假设，即肠道微生物区系调节鞘磷脂代谢物- 肠道CSN8/SphK1途径和携带鞘磷脂的肠道EVS的生物生成和释放 代谢产物(神经酰胺和S1P)转移到肝脏，进而吸引巨噬细胞进入肝脏。 促进非酒精性脂肪肝的肝损伤。重要的是，该提案还进行了翻译研究，以审查 针对肠道微生物区系和SphK1-S1PR1的营养纳米粒治疗干预的疗效 抑制作用于减轻肠肝轴改变。为了解决我们的假设，我们提出了以下具体目标： 目的1：确定肠源性EVS-S1P是否通过CSN8/SphK1途径调节肝脏炎症和损伤 在NAFLD。目的2：确定肠源性EVS-S1P是否对肝巨噬细胞有贡献 S1PR1-STAT3在NAFLD中的招募/激活。目标3：确定CSN8和CSN8的分子机制 SphK1对CSN8/S1P-S1PR1信号的相互调控和调制将阻止巨噬细胞 NAFLD的介导性肝损伤。该提案将提供对饮食-肠道-肝脏相互作用的更好理解，并 EVS-S1P诱导的肝脏炎症和损伤的分子机制。这个 研究将导致确定新的治疗靶点和潜在的饮食干预治疗NAFLD。

The overarching theme of this project is to address the mechanisms underlying gut derived extracellular vesicles (EVs)-induced liver inflammation/injury in Non-alcoholic fatty liver disease (NAFLD). We will determine the role of sphingolipid metabolites, specifically; Sphingosine 1-phosphate (S1P)-enriched gut EVs and pathway CSN8/SphK1 in the development of NAFLD. The current proposal links gut-derived EVs to macrophage- mediated inflammation by proposing that extracellular vesicles from gut recruit macrophages to the liver, resulting in liver injury and inflammation. Our recent work has begun to identify intestinal inflammation-induced alterations in EVs, and shows that gut-derived EVs play a critical role in the regulation of NKT cells and Th17 cells in the development of liver inflammation and colon cancer via gut-liver axis. Our preliminary data shows that LPS promotes Intestinal epithelial cells (IECs) release sphingolipid metabolites-enriched pro-inflammatory EVs including ceramide and S1P. Our preliminary findings also indicate that CSN8/SphK1 signaling pathway plays a crucial role in the production of S1P-enriched EVs. Chronic high fat diet consumption leads to increased gut permeability and expose the liver to gut-derived products including EVs of IECs. Increased S1P-enriched EVs activate its receptor S1P1 on hepatic macrophages, which may promote macrophage chemotaxis into the liver. This has led to the central hypothesis that gut microbiota regulate sphingolipid metabolites- enriched EVs biogenesis and release via gut CSN8/SphK1 pathway and gut EVs carrying sphingolipid metabolites (ceramide and S1P) translocate to liver, which in turn attract macrophages into the liver promoting liver injury in NAFLD. Importantly, the proposal also pursues translational studies that examine the efficacy of nutrition-nanoparticles based therapeutic interventions targeted at gut microbiota and SphK1-S1PR1 inhibition in mitigating gut-liver axis changes. To address our hypothesis, we propose the following specific aims: Aim 1: Determine whether gut-derived EVs-S1P regulate liver inflammation and injury via CSN8/SphK1 pathway in NAFLD. Aim 2: Determine whether gut-derived EVs-S1P contribute to liver macrophages recruitment/activation by S1PR1-STAT3 in NAFLD. Aim 3: Define molecular mechanisms underlying CSN8 and SphK1 reciprocal regulation and modulation of the CSN8/S1P-S1PR1 signal will prevent macrophages mediated-liver injury in NAFLD. The proposal will provide a better understanding of diet-gut-liver interactions and molecular mechanisms contributing to the pathogenesis of EVs-S1P-induced liver inflammation and injury. The study will lead to identification of new therapeutic targets and potential dietary interventions for treating NAFLD.