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

• 批准号: 10517197
• 负责人: Zhong-Bin Deng
• 金额: $ 41.32万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517197
• 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; Epithelial Cells; Farber' s lipogranulomatosis; Fatty Acids; Fatty Liver; Functional disorder; Gangliosides; Glycolipids; Glycosphingolipids; Hepatic; High Fat Diet; Immune; Immune system; Inflammation; Inflammatory; Intervention; Intestines; Lead; Ligands; Lipids; Liver; Mediating; Metabolism; Mucins; Mucous body substance; Mus; Obesity; Pathogenicity; Pathologic; Pathway interactions; Polysaccharides; Prevention; Production; Receptor Activation; Receptor Signaling; Regulation; Role; Sampling; Secretor blood group alpha-2-fucosyltransferase; Sphingolipids; Sphingosine; Stimulus; Stress; Therapeutic Effect; Therapeutic Intervention; Tight Junctions; Toll-like receptors; Up-Regulation; Xenobiotics; adherent junction; base; 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; macrophage; microbial; microbial host; microbiota; new therapeutic target; non-alcoholic fatty liver disease; pathogenic bacteria; prebiotics; prevent; response; sphingosine kinase; symbiont; translational study

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”在肝硬化中起着关键的致病作用。 非酒精性脂肪性肝病（NAFLD）。肠源性内毒素渗漏增加， 病理状况，包括高脂饮食（HFD）消耗。肠道岩藻糖基化是维持 肠道和其微生物群之间的平衡关系。然而，目前还不清楚宿主岩藻糖基化是如何发生的。 机械有助于肥胖相关的肠屏障功能，微生物易位和炎症。 鞘糖脂（GSL）是肠上皮细胞的主要成分，由与脂质结合的聚糖组成 （神经酰胺）核。神经酰胺是鞘脂代谢的中心，水解产生鞘氨醇 和脂肪酸通过神经酰胺酶包括中性神经酰胺酶（NcDase）。然而，肠NcDase是否 导致NAFLD中肠岩藻糖基化的原因尚不清楚。我们发现肠上皮细胞的缺失 （IEC）NcDase诱导响应HFD暴露的肠岩藻糖基化显著上调。我们 初步研究进一步证实HFD喂养的NcDase-/-小鼠具有肠AhR活性的增加， IL-22分泌和岩藻糖基化神经节苷脂（岩藻糖基-GM 1）的产生。我们还发现岩藻糖基-GM 1 可结合DC-SIGN（一种C型凝集素，在肝巨噬细胞中表达），并可诱导抗炎M2 巨噬细胞这导致了核心假设，即肠道NcDase调节肠道岩藻糖基化 以及随后通过IEC AhR信号的屏障功能;并且IEC NcDase衍生的岩藻糖基化 鞘糖脂通过岩藻糖基-GM 1/DC-SIGN途径诱导肝巨噬细胞极化， 防止NAFLD的发展。重要的是，该提案还追求翻译研究， 益生元2′-FL喂养和岩藻糖基-GM 1治疗靶向肠道岩藻糖基化和肝脏的功效 炎症巨噬细胞减轻肠-肝轴的变化。将实现以下具体目标： 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 完整我们将确定与NcDase相关的肠道微生物群对肠道岩藻糖基化和屏障的影响。 功能目的2：确定IEC AhR的NcDase调节是否有助于通过微生物介导的肠道岩藻糖基化 代谢产物的反应HFD暴露。目的3：确定IEC NcD酶衍生的岩藻糖基化 神经节苷脂有助于诱导肝耐受原性巨噬细胞，并评估 基于岩藻糖基化的NAFLD治疗干预。我们对NcDase介导的肠道岩藻糖基化的研究 益生元干预可能会带来新的机制理解，并确定新的治疗靶点 预防和治疗NAFLD。