Role of SMPDL3B in obesity-associated non-alcoholic fatty liver disease

SMPDL3B 在肥胖相关非酒精性脂肪肝中的作用

基本信息

批准号：
10538925
负责人：
Shuxia Wang
金额：
$ 49.14万
依托单位：
UNIVERSITY OF KENTUCKY
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：
2022-07-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10538925
关键词：
3-Dimensional Acids Affect Animal Model Animals Attenuated Back Binding CD36 Antigens CD36 gene Cell membrane Ceramides Data Development Diet Disease Disease Progression Down-Regulation Epidemic Fatty Liver Feedback Feeds Fibrosis GPI Membrane Anchors Human In Vitro Inflammation Inflammatory Knock-out Knowledge Kupffer Cells Lead Lipids Liver Liver Fibrosis Liver diseases Macrophage Activation Mediating Membrane Lipids Membrane Microdomains Membrane Proteins Metabolic Diseases Modeling Modification Obesity Organoids Pathogenesis Pathway interactions Patients Peptides Phenotype Process Production Proteins Reducing diet Risk Factors Rodent Role Signal Transduction Sphingomyelinase TLR4 gene Testing Therapeutic Thrombospondin 1 Western World base chronic liver disease cytokine in vitro Model in vivo knock-down macrophage monocyte mouse model nanoparticle new therapeutic target non-alcoholic fatty liver non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutic intervention novel therapeutics obesity treatment overexpression peripheral blood receptor recruit targeted treatment therapy development

项目摘要

Obesity is an independent risk factor for development of non-alcoholic fatty liver disease (NAFLD). With the epidemic burden of obesity and metabolic diseases, NAFLD occurrence is steadily rising, along with the need for therapeutic options of this disease. Preliminary data from rodent and human studies provide strong evidence to support the hypothesis that monocyte/macrophage-derived TSP1 in obesity downregulates liver macrophage SMPDL3B and this downregulation feeds back to increase TSP1 binding to its receptor-CD36. This positive feedback loop together with SMPDL3B’s action on TLR pathways further amplifies liver macrophage pro-inflammatory signaling and leads to NAFLD progression. In this proposal, how SMPDL3B regulates CD36 function and then TSP1-CD36 dependent pro-inflammatory signaling in macrophages will be determined in Aim 1. The in vivo importance of macrophage SMPDL3B in NAFLD development and progression in both animal models and human liver organoids will be determined in Aim 2. Whether specific blockade of TSP1/CD36 interaction upregulates liver macrophage SMPDL3B and attenuates liver pro- inflammatory signaling and NAFLD development and progression will be determined in Aim 3. Completing these studies will provide novel information on the mechanisms by which suppressed macrophage SMPDL3B enhances liver macrophage pro-inflammatory signaling and its critical role in the progression of obesity- associated NAFLD to NASH. Further, testing a novel therapeutic application of a peptide nanoparticle conjugate to block TSP1/CD36 interaction in obesity-associated NASH in vivo will have translational significance.

肥胖是发生非酒精性脂肪肝（NAFLD）的独立危险因素。随着肥胖和代谢疾病的流行负担，NAFLD 的发生率正在稳步上升，同时对来自啮齿动物和人类研究的初步数据为这种疾病的治疗选择提供了强有力的证据。支持肥胖中单核细胞/巨噬细胞衍生的 TSP1 下调肝脏这一假设的证据巨噬细胞 SMPDL3B 的下调会反馈增加 TSP1 与其受体 CD36 的结合。这种正反馈回路与 SMPDL3B 对 TLR 通路的作用一起进一步增强肝脏功能在此提议中，SMPDL3B 是如何影响巨噬细胞促炎症信号转导并导致 NAFLD 进展的。调节 CD36 功能，然后巨噬细胞中 TSP1-CD36 依赖性促炎信号传导将被目标 1 中确定的巨噬细胞 SMPDL3B 在 NAFLD 发展和体内的重要性动物模型和人类肝脏类器官的进展将在目标 2 中确定。是否具体阻断 TSP1/CD36 相互作用会上调肝巨噬细胞 SMPDL3B 并减弱肝促炎症信号传导和 NAFLD 的发生和进展将在目标 3 中确定。完成这些研究将提供有关抑制巨噬细胞 SMPDL3B 的机制的新信息增强肝脏巨噬细胞促炎信号传导及其在肥胖进展中的关键作用此外，还测试了肽纳米颗粒的新型治疗应用。结合物阻断体内肥胖相关 NASH 中 TSP1/CD36 相互作用将具有转化作用意义。