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

总结 非酒精性脂肪性肝炎（NASH）是西方世界慢性肝病的最常见原因 并且是主要的全球健康问题，导致肝硬化和肝细胞癌（HCC）。缺乏一个 最佳治疗要求更好地理解NASH的分子发病机制， 调节分子和靶向治疗方法的发展。研究，由以前的支持 这一更新应用的周期，解开了一个新的作用，致癌基因星形胶质细胞升高基因-1/Metadherin （AEG-1/MTDH）促进NASH。AEG-1通过抑制PPARα诱导脂肪变性，从而抑制脂肪酸β-氧化 (FAO)，并促进脂肪酸合成酶的翻译，从而增加从头脂肪生成 （DNL）。此外，AEG-1激活NF-κB，一种主要的炎症调节因子。因此AEG-1发挥了关键作用 NASH和NASH-HCC。我们建立了肝细胞靶向纳米颗粒的治疗效果， 递送AEG-1 siRNA以抑制小鼠中HFD诱导的NASH。宏观经济在全球经济中发挥着举足轻重的作用， 通过调节脂肪细胞和肝细胞的功能来调节NASH的发病机制。我们最近记录了 AEG-1在调节巨噬细胞活化中起重要作用， 细胞（AEG-1 MACMAC）对N-亚硝基二乙胺（DEN）诱导的炎性HCC具有深刻的抗性。我们 目前初步研究证明，AEG-1 β-MAC小鼠也对HFD诱导的NASH具有抗性，并鉴定出 一种新的翻译后修饰，半胱氨酸棕榈酰化，是蛋白质翻译和NF-κ B所必需的。 AEG-1的κB激活功能。这些观察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 导致NASH发展，并靶向抑制巨噬细胞和肝细胞中的AEG-1 可能是NASH的有效治疗干预。使用相关小鼠模型和人类的实验 细胞将被执行，以解决这些假设。我们提出的研究将揭示AEG-1的新作用 在巨噬细胞和一种新的翻译后修饰调节AEG-1功能。多项临床试验 记录了通过RNA干扰（RNAi）策略抑制肝脏中基因表达的功效， 从而建立该策略在临床中管理NASH的潜在应用。我们 因此，所提出的研究具有重要的机理和转化意义。

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.