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：
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
项目类别：
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&apos 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

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，“肠叶轴”在非酒精性脂肪肝疾病（NAFLD）的发展。肠道衍生的内毒素泄漏在下面增加病理状况，包括高脂饮食（HFD）消费量。肠道岩藻糖基化是维持的关键力量肠道与其微生物群之间的稳态关系。尽管如此，目前尚不清楚宿主如何构造机械有助于与观测相关的肠道屏障功能，微生物易位和炎症。糖磷脂（GSLS）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）核心。神经酰胺是鞘脂代谢的中心，并被水解生成鞘氨醇通过神经酶在内的脂肪酸和脂肪酸，包括中性神经酰胺酶（NCDase）。但是，是否肠道NCDase NAFLD中有助于肠道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诱导的肠道葡萄糖基化的明显上调响应于HFD暴露。我们的初步研究进一步表明，HFD喂养的NCDase - / - 小鼠的肠AHR活性增加， IL-22分泌和岩藻糖基化的神经节蛋白（岩藻糖基-GM1）的产生。我们还发现岩藻糖基-GM1 可以与在肝巨噬细胞中表达的DC-SIGN（一种C型凝集素）结合，可以诱导抗炎M2 巨噬细胞。这导致了一个中心假设，即肠道NCD酶调节肠道葡萄糖基化以及随后通过IEC AHR信号的屏障函数；并且IECS NCDase衍生的岩藻糖基化糖磷脂脂通过岩藻糖基-GM1/DC-SIGN途径诱导肝巨噬细胞极化，并诱导肝巨噬细胞极化防止NAFLD的发展。重要的是，该提案还进行了转化研究，以检查针对肠道构成和肝化的益生元2'-FL进食和构素基-GM1治疗的效率减轻肠道轴的炎症巨噬细胞发生变化。将执行以下特定目标：目标 1：确定NCDase对肠道葡萄糖基化的影响以及该影响对肠壁的影响正直。我们将确定与NCDase相关的肠道微生物群对肠道岩藻糖苷和屏障的影响功能。 AIM 2：确定IEC AHR的NCDase调节是否有助于通过微生物造成肠道化的肠道化。响应HFD暴露的代谢产物。 AIM3：确定IEC NCDase衍生的脉络化是否是否神经节有助于诱导肝耐受性巨噬细胞，并评估基于NAFLD的基于偶生的治疗干预措施。我们对NCDase介导的肠道脉络化的研究益生元干预可能会带来新的机械理解并确定新的治疗靶标用于预防和治疗NAFLD。