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The role of neutral ceramidase in intestinal fucosylation and liver steatosis and inflammation

中性神经酰胺酶在肠道岩藻糖基化以及肝脏脂肪变性和炎症中的作用

基本信息

批准号：
10632084
负责人：
Zhong-Bin Deng
金额：
$ 40.59万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10632084
关键词：
Alcohols Anti-Inflammatory Agents Apical Aryl Hydrocarbon Receptor Bacteria Binding Butyrates C-Type Lectins CD209 gene Cells Ceramidase Ceramides Chronic Complex Consumption Data Development Endotoxemia Endotoxins Enterocytes Epithelial Cells Epithelium Farber&apos s lipogranulomatosis Fatty Acids Fatty Liver Functional disorder Gangliosides Glycolipids Glycosphingolipids Hepatic High Fat Diet Immune Immune system Inflammation Inflammatory Intervention Intestines Ligands Lipids Liver Macrophage Mediating Metabolism Mucins Mucous body substance Mus Obesity Pathogenicity Pathologic Pathway interactions Penetration Phosphorylation Polysaccharides Prevention Production Receptor Activation Receptor Signaling Regulation Role Sampling Secretor blood group alpha-2-fucosyltransferase Sphingolipids Sphingosine Stimulus Stress Symbiosis Therapeutic Effect Therapeutic Intervention Tight Junctions Toll-like receptors Up-Regulation Xenobiotics adherent junction efficacy evaluation feeding galactosylgalactosylglucosylceramidase gastrointestinal epithelium gene product glycosylation gut inflammation gut microbiota gut-liver axis interleukin-22 intestinal barrier intestinal epithelium liver inflammation liver injury microbial microbial host microbiota new therapeutic target non-alcoholic fatty liver disease pathogenic bacteria prebiotics prevent response sphingosine kinase symbiont translational study

项目摘要

There is an increasing evidence that demonstrates a critical pathogenic role for the “gut-liver axis” in the development of nonalcoholic fatty liver diseases (NAFLD). Gut-derived endotoxin leakiness is increased under pathological conditions, including high fat diet (HFD) consumption. Gut fucosylation is a key force in maintaining a homeostatic relationship between the gut and its microbiota. Nevertheless, it is unclear how host fucosylation machinery contributes to obesity-associated intestinal barrier function, microbial translocation and inflammation. Glycosphingolipids (GSLs) are major constituents of enterocytes and consist of glycans conjugated to a lipid (ceramide) core. Ceramide is at the center of sphingolipid metabolism, and is hydrolyzed to generate sphingosine and fatty acid by ceramidases including neutral ceramidase (NcDase). However, whether gut NcDase contributes to intestinal fucosylation in NAFLD is unclear. We found that deletion of intestinal epithelial cells (IECs) NcDase induced marked upregulation of intestinal fucosylation in response to HFD exposure. Our preliminary studies further demonstrated that HFD-fed NcDase-/- mice have increases in intestinal AhR activity, IL-22 secretion and the production of fucosylated gangliosides (fucosyl-GM1). We also found that fucosyl-GM1 can bind to DC-SIGN, a C-type lectin, expressed in hepatic macrophages and can induce anti-inflammatory M2 macrophage. This has led to the central hypothesis that gut NcDase regulates the intestinal fucosylation and subsequent barrier function via IEC AhR signal; and that IECs NcDase-derived fucosylated glycosphingolipids induce hepatic macrophage polarization via fucosyl-GM1/DC-SIGN pathway and prevent the development of NAFLD. Importantly, the proposal also pursues translational studies that examine the efficacy of prebiotic 2′-FL feeding and fucosyl-GM1 treatment targeted at intestinal fucosylation and hepatic inflammatory macrophages in mitigating gut-liver axis changes. Following specific aims will be carried out: Aim 1: Determine the impact of NcDase on the gut fucosylation and the effects of this impact on intestinal barrier integrity. We will determine the impact of NcDase-related gut microbiota on the gut fucosylaton and barrier function. Aim 2: Determine whether NcDase regulation of IEC AhR contributes to gut fucosylation via microbial metabolite in response to HFD exposure. Aim3: Determine whether IEC NcDase-derived fucosylated gangliosides contribute to the induction of liver tolerogenic macrophages and evaluate the efficacy of fucosylation-based therapeutic interventions in NAFLD. Our studies on the NcDase-mediated gut fucosylation and prebiotic intervention will likely bring new mechanistic understanding and identify new therapeutic targets for the prevention and treatment of NAFLD.

越来越多的证据表明，“肠-肝轴”在肝纤维化中起关键致病作用。非酒精性脂肪性肝病(NAFLD)的发展。在以下情况下，肠源性内毒素泄漏增加病理条件，包括高脂饮食(HFD)消费。肠道岩藻糖基化是维持肠道与其微生物区系之间的一种动态平衡关系。然而，目前还不清楚宿主岩藻糖基化是如何机械有助于肥胖相关的肠道屏障功能、微生物移位和炎症。鞘糖脂(GSLS)是肠细胞的主要成分，由连接到脂质上的多糖组成 (神经酰胺)芯。神经酰胺是鞘磷脂新陈代谢的中心，并被水解制得鞘氨醇。神经酰胺酶包括中性神经酰胺酶(NcDase)。然而，无论Gut NcDase 在NAFLD中对肠道岩藻糖基化的贡献尚不清楚。我们发现，肠道上皮细胞的缺失 (IECS)NcDase诱导肠道岩藻糖化显著上调，以回应HFD暴露。我们的初步研究进一步证明，喂食HFD的NcDase-/-小鼠肠道AhR活性增加， IL-22的分泌和岩藻糖化神经节苷脂(岩藻糖基GM1)的产生。我们还发现岩藻糖基GM1 能与肝巨噬细胞表达的C型凝集素DC-SIGN结合并诱导抗炎M2 巨噬细胞。这导致了一个中心假设，即肠道NcDase调节肠道岩藻糖化和随后通过IEC AhR信号的屏障功能；以及IECS NcDase衍生岩藻糖基化鞘糖脂通过岩藻糖基GM1/DC-SIGN途径诱导肝巨噬细胞极化预防非酒精性脂肪肝的发展。重要的是，该提案还进行了翻译研究，以审查益生素2‘-FL喂养联合岩藻糖基GM1治疗对肠道岩藻糖化和肝脏的影响炎性巨噬细胞在减轻肠-肝轴改变中的作用。将实现以下具体目标：目标 1：确定NcDase对肠道岩藻糖基化的影响以及这种影响对肠道屏障的影响正直。我们将确定与NcDase相关的肠道微生物区系对肠道岩藻糖苷和屏障的影响功能。目的2：确定NcDase对IEC AhR的调节是否通过微生物促进肠道岩藻糖基化对HFD暴露的反应代谢物。目的：确定IEC NcDase衍生的岩藻糖基化神经节苷脂对肝脏耐受巨噬细胞的诱导作用及疗效评价基于岩藻糖基化的非酒精性脂肪肝的治疗干预。NcDase介导的肠道岩藻糖基化的研究益生菌干预可能带来新的机制理解和确定新的治疗靶点用于预防和治疗非酒精性脂肪肝。