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

CSN8 调节富含 S1P 的细胞外囊泡通过肠肝轴调节 NAFLD

• 批准号: 10392896
• 负责人: Zhong-Bin Deng
• 金额: $ 39.06万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-20 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392896
• 关键词: Address; Affect; Biogenesis; Cell physiology; Cells; Ceramides; Chemotaxis; Chronic; Colitis; Colon Carcinoma; Consumption; Data; Development; Diet; Dietary Intervention; Distant; Enzymes; Epithelial Cells; Hepatic; High Fat Diet; Immune; Inflammation; Inflammatory; Injury; Intestinal permeability; Intestines; Kupffer Cells; Link; Lipids; Liver; Macrophage Activation; Mediating; Molecular; Pathogenesis; Pathogenicity; Pathway interactions; Play; Production; Property; Regulation; Role; SPHK1 enzyme; STAT3 gene; Severities; Signal Pathway; Signal Transduction; Sphingolipids; TLR4 gene; Testing; Therapeutic; Therapeutic Intervention; Up-Regulation; Work; base; ceramide 1-phosphate; dietary; edg-1 Protein; efficacy evaluation; exosome; extracellular vesicles; gut inflammation; gut microbiota; gut-liver axis; interest; intestinal epithelium; liver development; liver inflammation; liver injury; lymphocyte trafficking; macrophage; microorganism antigen; nanoparticle; new therapeutic target; non-alcoholic fatty liver disease; nutrition; prevent; recruit; sphingosine 1-phosphate; translational study

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.

该项目的总体主题是解决肠道外囊泡的基础机制 （EV）诱导的非酒精性脂肪肝病（NAFLD）诱导的肝炎/损伤。我们将确定角色 特别是鞘脂代谢物； 1-磷酸盐（S1P）富含肠道电动汽车和途径 CSN8/SPHK1在NAFLD的开发中。当前的提案将肠道衍生的电动汽车与巨噬细胞联系起来 通过提出肠外囊泡从肠道募集巨噬细胞到肝脏的介导的炎症， 导致肝损伤和炎症。我们最近的工作已经开始识别肠道炎症引起的 电动汽车的改变，并表明肠道衍生的电动汽车在NKT细胞和TH17的调节中起关键作用 通过肠肝轴发育肝炎和结肠癌的开发细胞。我们的初步数据显示 LPS促进肠上皮细胞（IEC）释放了富含促炎的鞘脂代谢产物 包括神经酰胺和S1P在内的电动汽车。我们的初步发现还表明CSN8/SPHK1信号通路 在富含S1P的电动汽车的生产中起着至关重要的作用。慢性高脂饮食消耗导致增加 肠道渗透性并将肝脏暴露于包括IEC的电动汽车在内的肠道衍生产品。增加了S1P富集 EV在肝巨噬细胞上激活其受体S1P1，这可能会促进巨噬细胞趋化性 肝。这导致了一个中心假设，即肠道菌群调节鞘脂代谢物 - 通过肠道CSN8/SPHK1途径富集EV的生物发生和释放 代谢物（神经酰胺和S1P）转移到肝脏，肝脏又吸引了巨噬细胞进入肝脏 促进NAFLD的肝损伤。重要的是，该提案还进行了转化研究，研究了 针对肠道菌群和SPHK1-S1PR1的基于营养 - 纳米颗粒的治疗干预措施的功效 抑制肠道轴变化。为了解决我们的假设，我们提出以下具体目的： 目标1：确定肠道衍生的EVS-S1P是否通过CSN8/SPHK1途径调节肝脏炎症和损伤 在Nafld。 AIM 2：确定肠道衍生的EVS-S1P是否有助于肝巨噬细胞 s1pr1-stat3在NAFLD中招募/激活。 AIM 3：定义CSN8和 CSN8/S1P-S1PR1信号的SPHK1相互调控和调节将防止巨噬细胞 NAFLD中介导的肝损伤。该提案将更好地理解饮食中的肝脏相互作用和 有助于EVS-S1P诱导的肝脏炎症和损伤的发病机理的分子机制。这 研究将导致确定新的治疗靶标和治疗NAFLD的潜在饮食干预措施。

项目成果

Neutral ceramidase-dependent regulation of macrophage metabolism directs intestinal immune homeostasis and controls enteric infection.

• DOI: 10.1016/j.celrep.2022.110560
• 发表时间: 2022-03-29
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Sun, Rui;Gu, Xuemei;Lei, Chao;Chen, Liang;Chu, Shenghui;Xu, Guangzhong;Doll, Mark A.;Tan, Yi;Feng, Wenke;Siskind, Leah;McClain, Craig J.;Deng, Zhongbin
• 通讯作者: Deng, Zhongbin