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

AEG-1 在 NASH 和 NASH-HCC 中的作用

基本信息

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
项目类别：
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

项目摘要

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 (NAFLD)，范围从非酒精性脂肪肝 (NAFL) 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。它可导致肝硬化和肝细胞癌 (HCC)，并且与肝细胞增多独立相关。因心血管和肝脏疾病而死亡的风险。食用高脂肪和含有胆固醇的饮食，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，导致临床上多种介入方法的评估试验。然而，最佳疗法尚未开发，需要更深入的了解 NAFLD 的分子发病机制、调节该过程和发展的新分子的鉴定的靶向治疗方法。我们揭示了星形胶质细胞升高基因 1（也称为麦粘素 (MTDH) 和 LYRIC，用于 NASH。具有肝细胞特异性过度表达的转基因小鼠 AEG-1 (Alb/AEG-1) 会产生自发性 NASH。 NASH 患者的 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) 对高脂肪饮食 (HFD) 诱导的脂肪变性具有显着的抵抗力。这些发现表明AEG-1可能在调节NASH的发生和进展中发挥关键作用。长期来看本提案的目的是深入了解 NASH 的分子机制，以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 NASH 的潜在干预策略。我们假设多种事件，例如优先抑制核受体、脂质代谢调节基因的翻译调控和激活炎症，可能会导致 AEG-1 诱导的 NASH，而 AEG-1 抑制可能会干扰所有这些从而抑制 NASH 的发生和进展。具有综合功能、生化和将进行分子分析来解决这些假设。顺利完成拟议的研究将深入了解AEG-1促进NASH的分子机制并帮助确立 AEG-1 抑制作为 NASH 和 NASH-HCC 的潜在有效治疗策略。因此该提案具有很高的机制和转化意义。