Integrating LncRNA to Methionine Metabolism in Alcoholic Fatty Liver

将 LncRNA 整合到酒精性脂肪肝中的蛋氨酸代谢中

• 批准号: 9788177
• 负责人: Zhihong Yang
• 金额: $ 16.14万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788177
• 关键词: Adult; Affect; Alcohol consumption; Alcoholic Fatty Liver; Alcoholic Hepatitis; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcohols; Alleles; Biochemical Pathway; Chronic Hepatitis; Data; Development; Diabetes Mellitus; Ethanol; Expression Profiling; Fatty Liver; Fetal Liver; Functional disorder; H19 gene; Health; Hepatic; Hepatocyte; Homocysteine; Human; Hyperhomocysteinemia; Impairment; Injury; Investigation; Knockout Mice; Lipids; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Mediating; Metabolism; Methionine; Methionine Metabolism Pathway; MicroRNAs; Mission; Modeling; Molecular; Molecular Biology; Morbidity - disease rate; Mus; National Institute on Alcohol Abuse and Alcoholism; Neoplasm Metastasis; Obesity; Pathologic; Physiological; Plasma; Polypyrimidine Tract-Binding Protein; Porifera; Prevalence; Primary carcinoma of the liver cells; RNA-Binding Proteins; Regulation; Reporting; Research; Role; Safety; Systems Biology; Testing; Time; United States; Untranslated RNA; base; betaine-homocysteine methyltransferase; chronic alcohol ingestion; chronic liver disease; clinically relevant; clinically significant; experience; genome-wide; in vivo; innovation; interest; liver injury; liver metabolism; mRNA Stability; metabolomics; mortality; novel; overexpression; paternal imprint; tumor

Abstract Alcoholic liver disease (ALD) is one of the primary causes of morbidity and mortality in the United States, which ranges from alcoholic fatty liver (AFL), cirrhosis, to hepatocellular carcinoma. AFL is characterized by accumulation of lipid in hepatocytes, which represents the initial stage of ALD. Chronic alcohol consumption can cause abnormal homocysteine (Hcy) and methionine (Met) metabolism, which in turn contributes to the development and progression of AFL. LncRNA H19 is paternally imprinted lncRNA, and is highly expressed in fetal liver but diminishes in adult liver. Of particular interest, such expression is reactivated in human chronic liver disease, implicating an important regulatory role in hepatic function and metabolism. Our preliminary results demonstrated that hepatic overexpression of H19 promoted alcohol induced liver injury and steatosis, which was associated with altered hepatic TG profiling and methionine levels, as revealed by lipidomics and metabolomics analyses. However, the physiological and molecular action of H19 in AFL remains largely unexplored and warrants further investigation. The overall objective is to elucidate the mechanistic function of H19 in alcoholic fatty liver. The central hypothesis is that H19 interacts with RNA binding protein polypyrimidine tract-binding protein (PTBP1) to inhibit bataine- homocysteine S-methltransferase (BHMT) expression and function, which disrupts homocysteine and methionine metabolism, leading to alcoholic fatty liver. We propose two specific aims to test the central hypothesis. Aim #1: To characterize the physiological role of H19 in alcoholic fatty liver. Aim #2: To elucidate the molecular mechanisms by which H19 induces alcoholic fatty liver. The proposed studies build on our long-standing experiences in studying liver metabolism and disease. We propose to use combined approaches of molecular biology, systems biology, genome wide high throughput and metabolomics analysis to investigate the novel regulatory role of IncRNA H19 in AFL. Therefore, the proposed study would be a pioneering investigation in integrating lncRNA function with methionine metabolism in AFL, providing advanced understanding of the pathophysiology of AFL.

抽象的 酒精性肝病（ALD）是美国发病和死亡的主要原因之一， 其范围从酒精性脂肪肝（AFL）、肝硬化到肝细胞癌。 AFL 的特点是 肝细胞中脂质的积累，这代表了 ALD 的初始阶段。长期酗酒 食用可引起同型半胱氨酸（Hcy）和蛋氨酸（Met）代谢异常，进而 为 AFL 的发展和进步做出了贡献。 LncRNA H19 是父系印记的 lncRNA，并且 在胎儿肝脏中高表达，但在成人肝脏中表达减少。特别有趣的是，这样的表达是 在人类慢性肝病中重新激活，暗示对肝功能和肝功能的重要调节作用 代谢。我们的初步结果表明，H19 的肝脏过度表达会促进酒精 诱导肝损伤和脂肪变性，这与肝脏 TG 谱和蛋氨酸的改变有关 脂质组学和代谢组学分析揭示的水平。然而，生理学和分子学 H19 在 AFL 中的作用在很大程度上仍未被探索，值得进一步调查。总体目标是 阐明H19在酒精性脂肪肝中的机制功能。中心假设是H19 与 RNA 结合蛋白多聚嘧啶束结合蛋白 (PTBP1) 相互作用，抑制巴巴碱- 同型半胱氨酸 S-甲基转移酶 (BHMT) 的表达和功能，破坏同型半胱氨酸和 蛋氨酸代谢紊乱，导致酒精性脂肪肝。我们提出了两个具体目标来测试中央 假设。目标#1：表征 H19 在酒精性脂肪肝中的生理作用。目标#2： 阐明H19诱导酒精性脂肪肝的分子机制。拟议的研究建立 基于我们在研究肝脏代谢和疾病方面的长期经验。我们建议使用组合 分子生物学、系统生物学、全基因组高通量和代谢组学方法 分析研究 IncRNA H19 在 AFL 中的新调节作用。因此，拟议的研究 将是 AFL 中 lncRNA 功能与蛋氨酸代谢整合的开创性研究， 提供对 AFL 病理生理学的深入了解。