Integrating LncRNA to Methionine Metabolism in Alcoholic Fatty Liver

摘要 酒精性肝病（ALD）是美国发病率和死亡率的主要原因之一， 其范围从酒精性脂肪肝（AFL）、肝硬化到肝细胞癌。AFL的特点是 通过肝细胞中脂质的积累，这代表了ALD的初始阶段。慢性酒精 摄入可导致同型半胱氨酸（Hcy）和蛋氨酸（Met）代谢异常， 有助于AFL的发展和进展。lncRNA H19是父系印迹lncRNA，并且 在胎儿肝脏中高度表达，但在成人肝脏中减少。特别令人感兴趣的是， 在人类慢性肝病中重新激活，在肝功能中具有重要的调节作用， 新陈代谢.我们的初步结果表明，肝脏H19的过度表达促进酒精 诱导肝损伤和脂肪变性，这与改变肝脏TG谱和蛋氨酸 水平，如脂质组学和代谢组学分析所揭示。然而，生理和分子 H19在利武装部队中的作用在很大程度上仍未得到探索，需要进一步调查。总体目标是 探讨H19在酒精性脂肪肝中的作用机制。核心假设是H19 与RNA结合蛋白聚嘧啶片段结合蛋白（PTBP 1）相互作用，抑制bataine- 同型半胱氨酸S-甲基转移酶（BHMT）表达和功能，其破坏同型半胱氨酸， 蛋氨酸代谢，导致酒精性脂肪肝。我们提出了两个具体目标，以测试中央 假说.目的#1：描述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 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 分析以研究IncRNA H19在AFL中的新调节作用。因此，拟议的研究 将是整合lncRNA功能与AFL中甲硫氨酸代谢的开创性研究， 提供对AFL病理生理学的深入了解。

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.