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

肥胖是非酒精性脂肪性肝病（NAFLD）发展的独立危险因素。与 肥胖和代谢性疾病的流行负担，NAFLD的发生率稳步上升，沿着需要 这种疾病的治疗选择。啮齿动物和人类研究的初步数据提供了强有力的证据， 支持肥胖患者单核细胞/巨噬细胞来源的TSP 1下调肝脏的假说的证据 巨噬细胞SMPDL 3B，并且这种下调反馈增加了TSP 1与其受体-CD 36的结合。 这种正反馈循环与SMPDL 3B对TLR途径的作用一起进一步放大了肝脏的免疫反应。 巨噬细胞促炎信号传导并导致NAFLD进展。在本提案中，SMPDL 3B如何 调节CD 36功能，然后巨噬细胞中的TSP 1-CD 36依赖性促炎信号传导将被激活。 在目标1中确定。巨噬细胞SMPDL 3B在NAFLD发展中的体内重要性以及 在动物模型和人类肝脏类器官中的进展将在目标2中确定。无论是具体的 阻断TSP 1/CD 36相互作用可上调肝巨噬细胞SMPDL 3B，并减弱肝细胞增殖。 炎症信号传导和NAFLD发展和进展将在目标3中确定。完成 这些研究将提供关于抑制巨噬细胞SMPDL 3B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症进展中的关键作用- NAFLD与NASH相关。此外，测试肽纳米颗粒的新的治疗应用， 缀合物在体内阻断肥胖相关NASH中的TSP 1/CD 36相互作用将具有翻译活性。 意义

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.