Aldehydes in Alcohol-Induced Organ Injury

酒精引起的器官损伤中的醛

• 批准号: 8317630
• 负责人: Wei Jia
• 金额: $ 47.16万
• 依托单位: UNIVERSITY OF NORTH CAROLINA GREENSBORO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317630
• 关键词: 4 hydroxynonenal; Acetaldehyde; Alcohol consumption; Alcoholic Intoxication; Alcoholic Liver Diseases; Alcohols; Aldehydes; Attenuated; Biological Markers; Blood; Brain; Brain Injuries; Chronic; Development; Disease; Endotoxemia; Endotoxins; Enzymes; Epithelial; Epithelium; Ethanol Metabolism; Excision; FDA approved; Generations; Health; Hepatic; Hepatic Encephalopathy; Homeostasis; Inflammation; Inflammatory; Injury; Intestinal Content; Intestines; Knowledge; Lactobacillus acidophilus; Link; Lipid Peroxidation; Lipids; Lipopolysaccharides; Liver; Liver Dysfunction; Malondialdehyde; Measures; Mediating; Metabolic; Mitochondria; Molecular; Organ; Pathogenesis; Plasma; Play; Production; Proteins; Proteomics; Recombinants; Research; Resveratrol; Role; Signal Transduction; Source; Speed; Steatohepatitis; Supplementation; Testing; Therapeutic; Tight Junctions; Tissues; Toxic effect; Up-Regulation; Urine; Zinc; adduct; alcohol abuse therapy; alcohol exposure; aldehyde dehydrogenases; cytokine; cytotoxic; cytotoxicity; effective therapy; endoplasmic reticulum stress; gut microflora; intestinal epithelium; lipid metabolism; metabolomics; prevent; problem drinker; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Alcohol consumption exerts toxic effects on the body with liver and brain as the major target organs. Recent studies suggest that alcohol-induced organ injury may involve organ-organ interactions. The most well-known mechanism underlying organ-organ interactions is gut-generated endotoxin (lipopolysaccharide, LPS) signal. Alcohol consumption causes gut barrier disruption, leading to endotoxemia, which, in turn, causes tissue injury at the liver-brain axis by stimulating cytokine production. Aldehyde generation is a feature of alcohol intoxication. While alcohol metabolism generates acetaldehyde, lipid peroxidation produces lipid aldehydes such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). Accumulation of aldehydes has been detected in intestinal contents, liver, blood and brain after alcohol intoxication. Aldehydes are cytotoxic, and may mediate alcohol actions at the gut-liver-brain axis. First, acetaldehyde generation from the gut microflora critically mediate alcohol-induced gut barrier disruption and generation of LPS signal. Second, aldehydes generated from the liver have shown to mediate alcohol-induced liver injury by inactivating proteins. Third, liver dysfunction in aldehyde clearance results in systemic aldehyde elevation, which may act as a systemic factor and mediate alcohol-induced brain damage. Aldehydes can be detoxified primarily by ALDH in the liver, however, our studies showed that mitochondrial ALDH (ALDH2) was not up-regulated in the liver despite aldehyde accumulation after chronic alcohol exposure. We also found that zinc supplementation attenuated alcohol-induced liver injury in association with up-regulation of ALDH2. Over-expression of ALDH2 has been shown to attenuate mitochondrial and endoplasmic reticulum (ER) stress, thereby preventing alcohol-induced organs injury including liver and brain. This project will test our hypothesis that aldehydes critically mediate alcohol-induced cytotoxicity at the gut-liver-brain axis, thereby being a systemic factor in alcohol-induced pathogenesis. Aim 1 is to define the role of microbiota aldehyde generation in alcohol-induced gut barrier disruption and generation of LPS signal. Effects of gut luminal aldehydes on gut tight junctions, blood LPS and liver-brain injury will be determined. Metabolic alterations in the gut luminal contents and epithelium will also be measured. Aim 2 is to determine the significance of hepatic aldehyde generation in alcohol-induced liver injury. Effects of aldehydes on hepatic lipid homeostasis and pro-inflammatory cytokine production will be determined. Interaction between aldehydes and LPS in pro-inflammatory cytokine production will also be measured. Mechanistic link of aldehydes with alcohol-induced metabolomic and proteomic alterations in the liver will be identified. Aim 3 is to determine the significance of liver-generated aldehyde signal in alcohol-induced brain injury. The link between liver dysfunction and systemic aldehyde elevation will be defined. The role of liver- generated aldehyde signal in alcohol-induced brain injury will be determined. Aim 4 is to explore the molecular mechanism of aldehyde toxicity and aldehyde removal therapies. Formation of aldehyde-protein adducts at the gut-liver-brain axis will be identified. Effects of ALDH2-recombinant L. acidophilus, zinc and resveratrol on aldehyde clearance and alcohol-induced organ injury will be determined. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: Alcohol intoxication causes multiple organ injury, but FDA-approved effective therapy is not available. Alcohol metabolism generates aldehydes which are cytotoxic. Aldehyde generation in the intestine disrupts gut barrier, leading to endotoxemia which triggers inflammation. Liver dysfunction in aldehyde clearance will cause aldehyde accumulation in the liver and blood, leading to multiple organ injury. This project will define the role of aldehyde as a systemic factor in mediating alcohol-induced tissue damage at the gut-liver-brain axis. The proposed research will not only advance our knowledge on alcohol-induced pathogenesis, but also suggest the removal of aldehydes as a potential therapeutic strategy for treatment of alcohol-induced diseases.

描述（申请人提供）：饮酒对身体有毒性作用，以肝脏和大脑为主要靶器官。最近的研究表明，酒精引起的器官损伤可能涉及器官间的相互作用。最著名的器官-器官相互作用的机制是肠道产生的内毒素（脂多糖，LPS）信号。饮酒会破坏肠道屏障，导致内毒素血症，而内毒素血症反过来又会刺激细胞因子的产生，从而导致肝脑轴的组织损伤。醛生成是酒精中毒的一个特征。酒精代谢产生乙醛，脂质过氧化产生脂质醛，如4-羟基壬烯醛（4-HNE）和丙二醛（MDA）。酒精中毒后，在肠内容物、肝脏、血液和大脑中发现了醛的积累。醛类具有细胞毒性，可能介导酒精在肠-肝-脑轴的作用。首先，肠道菌群产生的乙醛介导酒精诱导的肠道屏障破坏和LPS信号的产生。其次，由肝脏产生的醛已被证明通过使蛋白质失活介导酒精诱导的肝损伤。第三，乙醛清除的肝功能障碍导致全身性乙醛升高，这可能是一个全身性因素，介导酒精性脑损伤。醛主要通过肝脏中的ALDH解毒，然而，我们的研究表明，尽管慢性酒精暴露后醛积累，但肝脏中的线粒体ALDH （ALDH2）并未上调。我们还发现补充锌可以减轻酒精诱导的肝损伤，这与ALDH2的上调有关。ALDH2的过度表达已被证明可以减轻线粒体和内质网（ER）应激，从而防止酒精诱导的器官损伤，包括肝和脑。该项目将验证我们的假设，即醛在肠-肝-脑轴上介导酒精诱导的细胞毒性，从而成为酒精诱导的发病机制中的一个系统性因素。目的1是确定微生物群醛生成在酒精诱导的肠道屏障破坏和LPS信号生成中的作用。确定肠腔醛对肠紧密连接、血脂多糖和肝脑损伤的影响。肠道内容物和上皮的代谢变化也将被测量。目的2：探讨肝醛生成在酒精性肝损伤中的意义。醛类对肝脂质稳态和促炎细胞因子产生的影响将被确定。醛和脂多糖在促炎细胞因子生产中的相互作用也将被测量。将确定醛与酒精诱导的肝脏代谢组学和蛋白质组学改变的机制联系。目的3：探讨肝生成醛信号在酒精性脑损伤中的意义。肝功能障碍和全身性醛升高之间的联系将被确定。肝生成的醛信号在酒精性脑损伤中的作用将被确定。目的四是探讨乙醛毒性的分子机制和脱醛治疗。醛蛋白加合物在肠-肝-脑轴的形成将被确定。确定aldh2重组嗜酸乳杆菌、锌和白藜芦醇对醛清除和酒精性器官损伤的影响。小灵通398/2590 （Rev. 06/09）页延续格式页