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.

总结