Systemic Oxidized Phospholipids in Mitochondrial Dysfunction of Alcoholic Injury

酒精损伤线粒体功能障碍中的全身氧化磷脂

• 批准号: 8318216
• 负责人: Thomas M McIntyre
• 金额: $ 39万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318216
• 关键词: ALOX15 gene; Affect; Alcohol consumption; Alcohols; Animal Feed; Animals; Apoptosis; Arachidonate 15-Lipoxygenase; Blood Circulation; Catabolism; Cells; Chronic; Clinic; Diagnosis; Diet; Disease; Distal; Enzymes; Ethanol; Ethanol Metabolism; Event; Free Radicals; Future; Generations; Hepatocyte; Human; Hydrogen Peroxide; In Situ; In Vitro; Inflammation Mediators; Inflammatory; Injury; Intercalated Cell; Kupffer Cells; Lecithin; Link; Lipids; Liver; Measures; Mitochondria; Molecular; Organ; Oxidative Stress; Patients; Phospholipids; Platelet Activating Factor; Process; Production; Public Health; Rattus; Reaction; Scheme; Severity of illness; Slice; Source; Steatohepatitis; Structure; Syndrome; Testing; Tissues; alcohol exposure; cell type; improved; in vivo; liver biopsy; liver function; liver metabolism; mitochondrial dysfunction; mitochondrial membrane; novel; oxidation; oxidized lipid; problem drinker; progression marker; trafficking

Ethanol metabolism generates oxidative stress and chronic ethanol exposure alters mitochondrial function. The central question extant is what events and processes link alcohol-induced mitochondrial dysfunction and ROS generation to local and distal tissue damage. We do not yet know how mitochondria are damaged by ethanol metabolism and ROS formation, the molecular identity(ies) of the toxic materials, nor their specific targets. How ethanol metabolism by the liver leads to damage to surrounding and distal tissue also remains opaque. We also lack reliable circulating markers of the propensity for tissue damage. We recently identified specific oxidatively-fragmented phospholipids that are readily transported into cells, where they intercalate into mitochondrial membranes to initiate mitochondrial-dependent apoptosis. We now find these lipids, the lipid inflammatory mediator Platelet-activating Factor (PAF), and distinctive hydroxylated phospholipids are all increased in the circulation of rats chronically ingesting ethanol. Early results suggest this occurs early in the human syndrome as well. These lipids are therefore circulating markers of endogenous oxidative processes resulting from liver metabolism of ethanol. Moreover, they themselves may induce proximal and distal tissue damage through dysregulation of their selective target, energized mitochondria. The aims of this proposal are: 1) Define the source, identity, and amounts of circulating lipid oxidation products circulating in animals and human chronically ingesting ethanol. 2) Determine how oxidized lipids affect mitochondrial function, and whether mitochondrial function is compromised in a cell specific fashion. 3) Determine whether PAF acetylhydrolase, an enzyme that specifically hydrolyzes oxidatively-modified phospholipids, protects mitochondrial function of liver cells during ethanol metabolism. Alcoholic liver and tissue damage is a significant public health issue, yet adequate markers of the progression of accruing damage are not available until late in the diease process. This project will validate novel circulating lipids as disease associated markers, but, significantly, because these same lipids induce tissue damage, we will be able to accurately assess future organ damage.

酒精代谢产生氧化应激，慢性酒精暴露改变 线粒体功能。现存的中心问题是事件和过程之间有什么联系 酒精所致线粒体功能障碍与局部和远端组织ROS的产生 损坏。我们还不知道乙醇代谢是如何破坏线粒体的。 和ROS的形成，有毒物质的分子同一性或它们的特异性 目标。肝脏乙醇代谢如何导致周围和远端损害 组织也仍然不透明。我们也缺乏可靠的循环标记的倾向 用于组织损伤。 我们最近发现了特定的氧化碎裂磷脂，这些磷脂很容易 运输到细胞内，在那里它们嵌入线粒体膜以启动 线粒体依赖性细胞凋亡。我们现在发现这些脂类，脂类发炎 介质血小板激活因子(PAF)和独特的羟化磷脂是 在长期摄入酒精的大鼠的循环中，所有这些都增加了。初步结果表明 这在人类综合症的早期也会发生。因此，这些脂类正在循环 乙醇肝脏代谢引起的内源性氧化过程的标记物。 此外，它们本身也可能通过以下途径引起近端和远端组织损伤 它们选择性靶标的失调，使线粒体充满活力。 该提案的目的是：1)确定流通领域的来源、身份和数量 长期摄入乙醇的动物和人类体内循环的脂质氧化产物。 2)确定氧化脂质如何影响线粒体功能，以及是否 线粒体的功能以细胞特有的方式受到损害。3)确定是否 PAF乙酰水解酶，一种专门降解氧化修饰的酶 磷脂，在乙醇代谢过程中保护肝细胞的线粒体功能。酒精性肝脏和组织损伤是一个重大的公共健康问题，但还不够 直到疾病晚期才能获得累积损害进展的标记 进程。该项目将验证新的循环血脂作为疾病相关标志物， 但是，值得注意的是，由于这些相同的脂类会导致组织损伤，我们将能够 准确评估未来的器官损伤。

项目成果

Platelet-activating factor receptor affects food intake and body weight.

血小板激活因子受体会影响食物摄入和体重。

• DOI: 10.1016/j.gendis.2015.06.002
• 发表时间: 2015-09
• 期刊: Genes & diseases
• 影响因子: 6.8
• 作者: Li W;McIntyre TM
• 通讯作者: McIntyre TM

Myeloperoxidase formation of PAF receptor ligands induces PAF receptor-dependent kidney injury during ethanol consumption.

• DOI: 10.1016/j.freeradbiomed.2015.05.020
• 发表时间: 2015-09
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Latchoumycandane C;Nagy LE;McIntyre TM
• 通讯作者: McIntyre TM