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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

基本信息

批准号：
9913998
负责人：
Zhong-Bin Deng
金额：
$ 40.36万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-20 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913998
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 Lymphocyte 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 edg-1 Protein exosome extracellular vesicles gut microbiota gut-liver axis inflammatory disease of the intestine interest intestinal epithelium liver development liver inflammation liver injury macrophage microorganism antigen nanoparticle new therapeutic target non-alcoholic fatty liver disease nutrition prevent recruit sphingosine 1-phosphate trafficking translational study

项目摘要

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.

本项目的首要主题是解决肠道衍生细胞外囊泡的机制