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

AEG-1 在 NASH 和 NASH-HCC 中的作用

• 批准号: 9321495
• 负责人: DEVANAND SARKAR
• 金额: $ 34.65万
• 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 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321495
• 关键词: Acids; Address; Affect; Astrocytes; Biochemical; Biological; Cardiovascular Diseases; Cessation of life; Cholesterol; Cirrhosis; Clinical Trials; Consumption; Dendrimers; Development; Diet; Down-Regulation; Enzymes; Evaluation; Event; Fatty acid glycerol esters; Gene Activation; Gene Expression Regulation; Genes; Genetic Transcription; Hepatocyte; High Fat Diet; Human; Hyperactive behavior; Individual; Inflammation; Inflammatory; Intervention; Knockout Mice; Lead; Liver; Liver diseases; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Molecular; Molecular Analysis; Mus; Nuclear Receptors; Nude Mice; Obesity; Oncogenes; Pathogenesis; Pathologic Processes; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Phenotype; Play; Polyethylene Glycols; Primary carcinoma of the liver cells; Process; Proteins; RNA Interference Therapy; RXR; Regulation; Resistance; Risk; Role; Small Interfering RNA; Steatohepatitis; Therapeutic; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; Translational Regulation; Translations; Treatment Efficacy; Up-Regulation; Western World; Work; Xenograft procedure; chronic liver disease; clinical application; insight; knock-down; lipid metabolism; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; novel therapeutics; overexpression; response; targeted treatment; transcription factor; western diet

Summary Nonalcoholic fatty liver disease (NAFLD), a spectrum extending from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), is the most common cause of chronic liver disease in the Western world. It can lead to cirrhosis and hepatocellular carcinoma (HCC) and is independently associated with an increased risk of death due to cardiovascular and liver diseases. Consumption of high fat and cholesterol containing diet, the Western diet, is an important determinant of obesity and hence NAFLD. The molecular mechanism of NAFLD is gradually being elucidated leading to the evaluation of multiple interventional approaches in clinical trials. However, the optimum therapy is yet to be developed mandating more in-depth understanding of molecular pathogenesis of NAFLD, identification of novel molecules regulating this process and development of targeted therapeutic approaches. We unravel a novel role of Astrocyte elevated gene-1, also known as metadherin (MTDH) and LYRIC, in NASH. A transgenic mouse with hepatocyte-specific overexpression of AEG-1 (Alb/AEG-1) develops spontaneous NASH. NASH patients show increased AEG-1 expression in their liver compared to normal individuals. On the other hand hepatocyte-specific conditional AEG-1 knockout mouse (AEG-1CKOHEP) shows significant resistance to high fat diet (HFD)-induced steatosis. These findings indicate that AEG-1 might play a pivotal role in regulating initiation and progression of NASH. The long term objective of the present proposal is to obtain in-depth understanding of the molecular mechanism of NASH to develop effective therapeutic strategies. The immediate objective is to comprehensively interrogate the molecular mechanism by which AEG-1 promotes NASH and NASH-HCC and evaluate AEG-1 inhibition as a potential interventional strategy for NASH. We hypothesize that multiple events, such as preferential inhibition of nuclear receptors, translational regulation of lipid metabolism regulating genes and activation of inflammation, might contribute to AEG-1-induced NASH and AEG-1 inhibition might interfere with all these events thereby inhibiting development and progression of NASH. A comprehensive functional, biochemical and molecular analyses will be performed to address these hypotheses. Successful completion of the proposed studies will provide in-depth insight into the molecular mechanism by which AEG-1 promotes NASH and help establish AEG-1 inhibition as a potential effective therapeutic strategy for NASH and NASH-HCC. Thus the proposal has high mechanistic and translational significance.

总结 非酒精性脂肪肝（NAFLD）是一种从非酒精性脂肪肝（NAFL）延伸到 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。 它可以导致肝硬化和肝细胞癌（HCC），并与肝细胞癌（HCC）的增加独立相关。 因心血管和肝脏疾病而死亡的风险。食用含高脂肪和胆固醇的饮食， 西方饮食是肥胖和NAFLD的重要决定因素。的分子机制 NAFLD逐渐被阐明，导致临床上对多种介入方法进行评价。 审判然而，最佳疗法尚未开发，需要更深入地了解 NAFLD的分子发病机制，调节这一过程的新分子的鉴定和发展 有针对性的治疗方法。我们揭示了星形胶质细胞升高基因-1的新作用，也称为 在NASH中，metadherin（MTDH）和LYRIC。一种肝细胞特异性过表达的转基因小鼠 AEG-1（Alb/AEG-1）发生自发性NASH。NASH患者在他们的组织中显示AEG-1表达增加， 肝脏与正常人相比。另一方面，肝细胞特异性条件性AEG-1敲除 小鼠（AEG-1CKOHEP）显示出对高脂饮食（HFD）诱导的脂肪变性的显著抗性。这些发现 提示AEG-1可能在NASH发生、发展过程中起重要作用。长期 本提案的目的是深入了解NASH的分子机制， 制定有效的治疗策略。当前的目标是全面审问 AEG-1促进NASH和NASH-HCC的分子机制，并评估AEG-1抑制作用作为一种免疫抑制剂。 NASH的潜在干预策略。我们假设多个事件，如优先抑制 核受体的转录调控、脂质代谢调节基因的翻译调控和 炎症可能导致AEG-1诱导的NASH，而AEG-1抑制可能会干扰所有这些 事件，从而抑制NASH的发展和进展。一种综合的功能性、生化性和 将进行分子分析以解决这些假设。圆满完成拟议的 研究将深入了解AEG-1促进NASH的分子机制， 建立AEG-1抑制作为NASH和NASH-HCC的潜在有效治疗策略。因此 建议具有很高的机械和翻译意义。