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

AEG-1 在 NASH 和 NASH-HCC 中的作用

• 批准号: 10784851
• 负责人: DEVANAND SARKAR
• 金额: $ 2.93万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-25 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10784851
• 关键词: Address; Adipocytes; Astrocytes; Cells; Cirrhosis; Clinic; Clinical Trials; Cysteine; Development; Diethylnitrosamine; Disease; Enzymes; Fatty Acids; Gene Expression; Genes; Hepatocyte; Human; Inflammation; Inflammatory; Liver; Macrophage; Macrophage Activation; Molecular; Mus; Myeloid Cells; Oncogenes; PPAR alpha; Pathogenesis; Play; Post-Translational Protein Processing; Primary carcinoma of the liver cells; Proteins; RNA Interference; Resistance; Role; Small Interfering RNA; Therapeutic; Therapeutic Intervention; Translations; Treatment Efficacy; Western World; chronic liver disease; experimental study; global health; insight; lipid biosynthesis; mouse model; nanoparticle delivery; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; oxidation; palmitoylation; targeted treatment; therapeutically effective

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.

概括 非酒精性脂肪性肝炎（NASH），这是西方世界慢性肝病的最常见原因 以及一个主要的全球健康问题，导致肝硬化和肝细胞癌（HCC）。缺乏 最佳治疗要求更好地理解NASH的分子发病机理，鉴定 监管分子和靶向治疗方法的发展。研究，由以前的支持 这种更新应用的循环，揭示了癌基因星形胶质细胞升高基因1/元粘着蛋白的新作用 （AEG-1/MTDH）促进NASH。 AEG-1通过抑制PPARα诱导脂肪变性，因此脂肪酸β-氧化 （粮农组织），并促进脂肪酸合成酶的翻译，从而增强从头脂肪生成 （DNL）。另外，AEG-1激活了炎症的主要调节剂NF-κB。 AEG-1起关键角色 在Nash和Nash-HCC中。我们确定了肝细胞靶向的纳米颗粒的治疗效率 输送AEG-1 siRNA以抑制小鼠HFD诱导的NASH。巨噬细胞在 NASH的发病机理通过衡量脂肪细胞和肝细胞的功能。我们最近记录了 AEG-1在调节巨噬细胞激活中起着至关重要的作用 细胞（AEG-1ΔMAC）对N-亚硝基二乙胺（DEN）诱导的炎症性HCC具有深远的抗性。我们的 现在的初步研究证明，AEG-1ΔMAC小鼠也对HFD诱导的NASH有抵抗力，并识别 蛋白质翻译和NF-需要一种新型的翻译后修饰，半胱氨酸棕榈酰化 AEG-1的κB激活函数。这些观察结果使我们可以假设巨噬细胞AEG-1 通过调节脂肪细胞和肝细胞来促进NASH，半胱氨酸棕榈酰化调节AEG-1功能 这有助于NASH的发展，并针对巨噬细胞中AEG-1的抑制作用 可能是纳什的有效治疗干预措施。使用相关鼠标和人类的实验 将进行细胞以解决这些假设。我们提出的研究将揭示AEG-1的新作用 在巨噬细胞和新颖的翻译后修饰调节AEG-1功能中。多次临床试验 通过RNA干扰（RNAi）策略抑制肝脏在肝脏中抑制基因表达的效率 疾病，从而建立了该策略在诊所管理NASH的潜在应用。我们的 因此，提出的研究具有重要的机械和翻译意义。