The role of AEG-1 in NASH and NASH-HCC

摘要 非酒精性脂肪性肝炎(NASH)，西方世界慢性肝病的最常见原因 和一个主要的全球健康问题，导致肝硬变和肝细胞癌(HCC)。缺乏一种 最佳治疗要求更好地了解NASH的分子发病机制，识别 调节分子和靶向治疗方法的发展。研究，由以前的支持 这一更新应用的循环，揭开了癌基因星形胶质细胞上调基因-1/金属粘附素的新作用 (AEG-1/MTDH)在促进NASH方面。AEG-1通过抑制PPARα诱导脂肪变性，从而导致脂肪酸β氧化 (粮农组织)，并促进脂肪酸合成酶的翻译，从而增强新生脂肪生成 (DNL)。此外，AEG-1激活了炎症的主要调节因子--核因子-κB。因此，AEG-1起着关键作用 在纳什和纳什-肝癌。我们确定了一种肝细胞靶向纳米颗粒的治疗效果 传递AEG-1 siRNA以抑制HFD诱导的小鼠NASH。巨噬细胞在这一过程中发挥着关键作用。 NASH的发病机制与调节脂肪细胞和肝细胞功能有关。我们最近记录了 AEG-1在调节巨噬细胞活化和髓系AEG-1缺失小鼠中的重要作用 细胞(AEG-1、∆、MAC)对N-亚硝基二乙胺(DEN)诱导的炎性肝癌具有深刻的抵抗力。我们的 目前的初步研究证明，AEG-1∆MAC小鼠也对高脂血症诱导的NASH具有抵抗力，并确定 蛋白质翻译和核因子需要一种新的翻译后修饰，半胱氨酸棕榈酰化。 κ-1的激活功能。这些观察结果使我们能够假设巨噬细胞AEG-1 通过调节脂肪细胞和肝细胞促进NASH，半胱氨酸棕榈酰化调节AEG-1功能 促进NASH的发生，并靶向抑制巨噬细胞和肝细胞的AEG-1 对NASH可能是一种有效的治疗干预。使用相关小鼠模型和人类进行的实验 将进行单元格来解决这些假设。我们提出的研究将揭开AEG-1的一个新角色 和一种新的调节AEG-1功能的翻译后修饰。多项临床试验 通过RNA干扰(RNAi)策略抑制肝脏中基因表达的有效性 从而建立了在诊所管理NASH的这一战略的潜在应用。我们的 因此，所提出的研究具有重要的机制意义和翻译意义。

Summary Nonalcoholic steatohepatitis (NASH), the most common cause of chronic liver disease in the Western world and a major global health problem, leads to cirrhosis and hepatocellular carcinoma (HCC). The lack of an optimum therapy mandates better understanding of the molecular pathogenesis of NASH, identification of regulatory molecules and development of targeted therapeutic approaches. Studies, supported by previous cycle of this renewal application, unraveled a novel role of the oncogene Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) in promoting NASH. AEG-1 induces steatosis by inhibiting PPARα, hence fatty acid β-oxidation (FAO), and promoting translation of fatty acid synthesizing enzymes thus augmenting de novo lipogenesis (DNL). Additionally, AEG-1 activates NF-κB, a master regulator of inflammation. Thus AEG-1 plays a key role in NASH and NASH-HCC. We established the therapeutic efficacy of a hepatocyte-targeted nanoparticle delivering AEG-1 siRNA to inhibit HFD-induced NASH in mice. Macrophages play a pivotal role in the pathogenesis of NASH by regulating the functions of adipocytes and hepatocytes. We recently documented that AEG-1 plays a vital role in regulating macrophage activation and mice with deletion of AEG-1 in myeloid cells (AEG-1∆MAC) are profoundly resistant to N-nitrosodiethylamine (DEN)-induced inflammatory HCC. Our preliminary studies now document that AEG-1∆MAC mice are also resistant to HFD-induced NASH, and identify that a novel post-translational modification, cysteine palmitoylation, is required for protein translation and NF- κB activation functions of AEG-1. These observations allow us to hypothesize that macrophage AEG-1 promotes NASH by regulating adipocytes and hepatocytes, cysteine palmitoylation regulates AEG-1 functions which contribute to NASH development, and targeted inhibition of AEG-1 in macrophages and hepatocytes might be an effective therapeutic intervention for NASH. Experiments using relevant mouse models and human cells will be performed to address these hypotheses. Our proposed studies will unravel a novel role of AEG-1 in macrophages and a novel post-translational modification regulating AEG-1 function. Multiple clinical trials document efficacy of inhibiting expression of genes in the liver by RNA interference (RNAi) strategy in a variety of diseases thereby establishing potential application of this strategy to manage NASH in the clinics. Our proposed studies thus have important mechanistic and translational significance.