The Role of Hepatic FMO3 in Ethanol Induced Liver Injury

肝脏 FMO3 在乙醇所致肝损伤中的作用

• 批准号: 8835660
• 负责人: Stephanie Marshall
• 金额: $ 5.15万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-08 至 2015-09-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835660
• 关键词: Acute; Address; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholism; Alcohols; Amines; Animal Model; Animals; Antisense Oligonucleotides; Apoptosis; Automobile Driving; Behavior; Blood; C57BL/6 Mouse; Cardiovascular Diseases; Cause of Death; Cells; Characteristics; Choline; Chronic; Data; Development; Diet; Diffuse; Disease; Endotoxins; Enzymes; Ethanol; Event; Fatty Liver; Fatty acid glycerol esters; Female; Flavins; Foamy Macrophage; Food; Future; G-Protein-Coupled Receptors; Generations; Genes; Health; Hepatic; Hepatocyte; Human; Immune; Immunity; Infiltration; Inflammation; Ingestion; Intestines; Knockout Mice; Levocarnitine; Life Style; Link; Lipids; Liver; Meat; Mediating; Metabolism; Mixed Function Oxygenases; Modeling; Morbidity - disease rate; Mus; Nutrient; Pathogenesis; Pathway interactions; Patients; Peripheral; Physiological; Plasma; Play; Prevention; Probiotics; Process; Production; Reporting; Risk; Role; Signal Pathway; Signal Transduction; Steatohepatitis; Stream; Taxon; Testing; Triglycerides; Work; base; dietary constituent; drug discovery; feeding; gut microbiota; lipid metabolism; liver function; macrophage; microbial; monocyte; mortality; mouse model; neutrophil; non-alcoholic; novel; pre-clinical; problem drinker; programs; public health relevance; receptor; response; trimethylamine; trimethyloxamine

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.

描述（由申请人提供）：酒精是归因于生活方式行为的死亡的主要原因之一。酒精中毒是一种多方面的疾病，可有害地对肝功能代谢甘油三酸酯和调节免疫细胞浸润的能力产生影响。尽管众所周知，酒精会促进内毒素从肠道含量到血流的易位，但尚不清楚这是否是唯一促进酒精诱导肝损伤的肠道信号。最近，涉及三甲胺（TMA）涉及肠道菌群依赖性产生的新途径以及随后TMA向三甲胺 - 氧化物（TMAO）的肝转化是小鼠中非酒精和酒精性肝病的关键成分。最近发现，呼吸TMA水平与人类患者的酒精性肝炎密切相关。此处提出的研究将全面分析新玩家在酒精性肝病（ALD）（黄素单加氧酶3，FMO3）中的作用，该疾病将TMA转换为肝脏中的TMAO。我们的研究将研究FMO3底物TMA的信号传导作用，在调节免疫细胞浸润，从而促进酒精性肝炎的进展。我们假设，当乙醇和饮食成分（例如胆碱和L-肉碱）被消耗时，肠道菌群会产生TMA。然后，该TMA扩散到血浆中，在该血浆中激活TAAR5（G蛋白偶联受体）。我们预计这会促进肝炎的特征，这会促进肝脏周围单核细胞和中性粒细胞的募集。在肝FMO3表达降低的情况下，我们将使用慢性乙醇诱导的肝损伤的标准小鼠模型来解决我们的假设。使用该模型，我们将研究TMA，TAAR5和肝FMO3在促进乙醇进食后促进肝免疫细胞浸润中的作用。我们的研究共同具有阐明TMA在促进多生物疾病过程中的作用的潜力，ALD。