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，对肝功能代谢甘油三酯和调节免疫细胞浸润的能力产生有害影响。虽然酒精促进内毒素从肠道内腔内容物转运到血流是众所周知的，但尚不清楚这是否是促进酒精诱导的肝损伤的唯一肠道源性信号。最近，一种涉及肠道微生物依赖的三甲胺（TMA）生成和随后肝脏将TMA转化为三甲胺氧化物（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一种新的参与者在酒精性肝病（ALD）（黄素单加氧酶3，FMO3）中的作用，该参与者将肝脏中的TMA转化为TMAO。我们的研究将探讨FMO3的底物TMA在调节免疫细胞浸润从而促进酒精性肝炎进展中的信号作用。我们假设，当乙醇和饮食成分，如胆碱和左旋肉碱，被消耗，肠道菌群产生TMA。然后这种TMA扩散到血浆中，在那里它激活了Taar5，一种G蛋白偶联受体。我们预计这会促进外周单核细胞和中性粒细胞向肝脏募集，这是酒精性肝炎的特征。我们将使用肝脏FMO3表达降低的慢性乙醇性肝损伤标准小鼠模型来验证我们的假设。利用该模型，我们将研究TMA、Taar5和肝脏FMO3在乙醇喂养时促进肝脏免疫细胞浸润的作用。总的来说，我们的研究具有阐明TMA在促进多有机体疾病过程（ALD）中的作用的潜力。

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.