The Role of Hepatic FMO3 in Ethanol Induced Liver Injury

描述（由申请人提供）：酒精是生活方式行为导致死亡的主要原因之一。酒精中毒是一种多方面的疾病，它对肝功能代谢甘油三酯和调节免疫细胞浸润的能力产生不良影响。虽然酒精促进了内毒素从肠腔内容物到血流的移位，但尚不清楚这是否是促进酒精诱导的肝损伤的唯一肠源性信号。最近，一种涉及肠道微生物群依赖性生成三甲胺（TMA）和随后将TMA转化为氧化三甲胺（TMAO）的新途径已被证明是小鼠非酒精性和酒精性肝病的关键组成部分。最近发现，呼吸TMA水平与人类患者的酒精性肝炎密切相关。本文提出的研究将全面分析酒精性肝病（ALD）中新的参与者（黄素单加氧酶3，FMO 3）的作用，它将TMA转化为肝脏中的TMAO。我们的研究将检查FMO 3的底物TMA在调节免疫细胞浸润中的信号作用，从而促进酒精性肝炎的进展。我们假设，当乙醇和饮食成分，如胆碱和L-肉碱，被消耗的肠道微生物群产生TMA。这种TMA然后扩散到血浆中，在那里它激活Taar 5，一种G蛋白偶联受体。我们预计，这促进了外周血单核细胞和中性粒细胞向肝脏的募集，这是酒精性肝炎的特征。我们将使用标准小鼠模型慢性乙醇诱导的肝损伤在肝脏FMO 3表达减少的情况下解决我们的假设。使用该模型，我们将研究TMA，Taar 5和肝脏FMO 3在乙醇喂养后促进肝脏免疫细胞浸润中的作用。总的来说，我们的研究有可能阐明TMA在促进多生物体疾病过程中的作用，ALD。

DESCRIPTION (provided by applicant): Alcohol is among the leading causes of death attributable to lifestyle behavior. Alcoholism is a multifaceted disease that deleteriously exerts ts effects on liver function's ability to metabolize triglyceride and to regulate immune cell infiltraion. Although it is well appreciated that alcohol promotes the translocation of endotoxin from the luminal contents of the intestine to the blood stream it is unclear whether this is the only gut derived signal that promotes alcohol induced liver injury. Recently, a novel pathway involving gut microbiota-dependent generation of trimethylamine (TMA) and subsequent hepatic conversion of TMA to trimethylamine-oxide (TMAO) has been shown to be a critical component of both non-alcoholic and alcoholic liver disease in mice. It was recently discovered that breath TMA levels strongly correlate with alcoholic hepatitis in human patients. Studies proposed here will comprehensively analyze the role of a new player in alcoholic liver disease (ALD) (flavin monooxygenase 3, FMO3), which converts TMA to TMAO in the liver. Our studies will examine the signaling role of FMO3's substrate, TMA, in regulating immune cell infiltration and thus promoting the progression of alcoholic hepatitis. We hypothesize that when ethanol and dietary constituents, such as choline and L-carnitine, are consumed the gut microbiota produce TMA. This TMA then diffuses into the plasma where it activates Taar5, a G protein-coupled receptor. We anticipate that this promotes the recruitment of peripheral monocytes and neutrophils to the liver, which are characteristic of alcoholic hepatitis. We will address our hypothesis using the standard mouse model of chronic ethanol-induced liver injury in the presence of reduced hepatic FMO3 expression. Using this model we will investigate the roles of TMA, Taar5 and hepatic FMO3 in promoting hepatic immune cell infiltration upon ethanol feeding. Collectively our studies hold the potential to elucidate the role of TMA in promoting a multiorganismal disease process, ALD.