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）是西方世界慢性肝病的最常见原因 一个主要的全球健康问题，导致肝硬化和肝细胞癌（HCC）。 最佳治疗要求更好地了解 NASH 的分子发病机制、识别 先前支持的调节分子和靶向治疗方法的开发。 这一更新应用的周期，揭示了癌基因星形胶质细胞升高基因-1/Metadherin的新作用 (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，从而增强脂肪从头生成 (DNL)。此外，AEG-1 激活炎症的主要调节因子 NF-κB，因此 AEG-1 起着关键作用。 我们确定了肝细胞靶向纳米颗粒的治疗功效。 递送 AEG-1 siRNA 抑制 HFD 诱导的小鼠 NASH 中的巨噬细胞发挥着关键作用。 我们最近记录了 NASH 的发病机制是通过调节脂肪细胞和肝细胞的功能来实现的。 表明 AEG-1 在调节巨噬细胞活化中起着至关重要的作用，并且骨髓中 AEG-1 缺失的小鼠 细胞 (AEG-1ΔMAC) 对 N-亚硝基二乙胺 (DEN) 诱导的炎症性 HCC 具有很强的抵抗力。 初步研究现在证明 AEG-1ΔMAC 小鼠也能抵抗 HFD 诱导的 NASH，并确定 蛋白质翻译和 NF-需要一种新的翻译后修饰，即半胱氨酸棕榈酰化 AEG-1 的 κB 激活功能这些观察结果使我们能够捕获巨噬细胞 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 有助于 NASH 的发展，并靶向抑制巨噬细胞和肝细胞中的 AEG-1 使用相关小鼠模型和人类进行的实验可能是 NASH 的有效治疗干预措施。 我们将进行细胞研究来解决这些假设。我们提出的研究将揭示 AEG-1 的新作用。 巨噬细胞和调节 AEG-1 功能的新型翻译后修饰 多项临床试验。 记录了通过 RNA 干扰 (RNAi) 策略抑制多种肝脏基因表达的功效 从而建立了该策略在诊所管理 NASH 的潜在应用。 因此，所提出的研究具有重要的机制和转化意义。