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.

概括 非酒精性脂肪肝病（NAFLD），从非酒精脂肪肝（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。 它可能导致肝硬化和肝细胞癌（HCC），并且与增加有关 由于心血管疾病和肝脏疾病而导致死亡的风险。消费高脂肪和含胆固醇的饮食， 西方饮食是肥胖和NAFLD的重要决定因素。分子机制 NAFLD逐渐被阐明，导致评估临床中多种介入方法 试验。但是，最佳疗法尚未开发出来，要求对 NAFLD的分子发病机理，调节这一过程和发育的新分子的鉴定 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 纳什（Nash）中的元丝蛋白（MTDH）和抒情诗。具有肝细胞特异性过表达的转基因小鼠 AEG-1（ALB/AEG-1）自发纳什。 NASH患者在其他们的AEG-1表达中增加了 与正常个体相比，肝脏。另一方面，肝细胞特定条件AEG-1敲除 小鼠（AEG-1CKOHEP）显示出对高脂肪饮食（HFD）诱导的脂肪变性的显着耐药性。这些发现 表明AEG-1可能在调节NASH的启动和进展中起关键作用。长期 本建议的目的是深入了解NASH的分子机制 制定有效的治疗策略。直接目标是全面审问 AEG-1促进NASH和NASH-HCC并评估AEG-1抑制作用的分子机制 纳什的潜在介入策略。我们假设多个事件，例如优先抑制 核受体，调节基因的脂质代谢的翻译调节和激活 炎症，可能导致AEG-1诱导的NASH和AEG-1抑制作用可能会干扰所有这些 事件因此抑制了纳什的发展和发展。全面的功能，生化和 将进行分子分析以解决这些假设。成功完成拟议的 研究将深入了解AEG-1促进NASH并帮助的分子机制 建立AEG-1抑制作用，作为NASH和NASH-HCC的潜在有效治疗策略。因此 提案具有很高的机械和转化意义。