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

肥胖是发展为非酒精性脂肪性肝病(NAFLD)的独立危险因素。与 肥胖和代谢性疾病的流行负担，非酒精性脂肪肝的发病率正在稳步上升，随着需求的增加 关于这种疾病的治疗选择。来自啮齿动物和人类研究的初步数据提供了强有力的 支持肥胖患者单核/巨噬细胞来源的TSP1下调肝脏功能的证据 巨噬细胞SMPDL3B和这种下调反馈增加TSP1与其受体CD36的结合。 这个正反馈环与SMPDL3B在TLR通路上的作用一起进一步放大肝脏 巨噬细胞的促炎信号并导致NAFLD的进展。在这份提案中，SMPDL3B如何 调节CD36功能，然后TSP1-CD36依赖巨噬细胞的促炎信号 巨噬细胞SMPDL3B在NAFLD发生和发展中的体内重要性 在动物模型和人类肝脏有机化合物中的进展将在目标2中确定。 阻断TSP1/CD36相互作用上调肝巨噬细胞SMPDL3B，抑制肝细胞病变 炎症信号和NAFLD的发展和进展将在目标3中确定。完成 这些研究将为抑制巨噬细胞SMPDL3B的机制提供新的信息 增强肝巨噬细胞促炎信号及其在肥胖进展中的关键作用 将NAFLD与NASH关联。此外，测试多肽纳米颗粒的一种新的治疗应用 结合阻断肥胖相关NASH体内TSP1/CD36的相互作用将具有翻译作用 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.