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: 7671505
• 负责人: Thomas M McIntyre
• 金额: $ 38.98万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7671505
• 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; Hydrolysis; 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

DESCRIPTION (provided by applicant): 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 application 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 disease 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.

描述（由申请人提供）：乙醇代谢产生氧化应激，慢性乙醇暴露会改变线粒体功能。现存的主要问题是，哪些事件和过程将酒精诱导的线粒体功能障碍和ROS产生与局部和远端组织损伤联系起来。我们尚不知道线粒体如何被乙醇代谢和ROS形成，有毒材料的分子身份（IES）或其特定靶标损害。肝脏的乙醇代谢如何导致周围和远端组织的损伤也仍然不透明。我们还缺乏可靠的循环标记，这些标记是组织损伤的倾向。我们最近确定了容易运输到细胞中的特定氧化磷脂，在那里它们插入了线粒体膜以启动线粒体依赖性细胞凋亡。现在，我们发现这些脂质，脂质炎症介质血小板激活因子（PAF）和独特的羟基化磷脂在长期摄入的乙醇的循环中都增加了。早期结果表明，这也发生在人类综合征的早期。因此，这些脂质是由乙醇肝代谢引起的内源性氧化过程的循环标记。此外，它们本身可能通过其选择性靶标线粒体能量障碍而引起近端和远端组织损伤。该应用的目的是1）定义动物和人类长期摄入乙醇的循环脂质氧化产物的来源，身份和量。 2）确定氧化的脂质如何影响线粒体功能，以及线粒体功能是否以细胞特异性方式损害。 3）确定PAF乙酰水合酶是一种特异性水解氧化磷脂的酶，可以保护乙醇代谢过程中肝细胞的线粒体功能。酒精性肝脏和组织损害是一个重大的公共卫生问题，但直到疾病过程后期才能获得应计损害进展的足够标志。该项目将验证新型的循环脂质作为疾病相关的标记，但要显着，因为这些相同的脂质会诱导组织损伤，我们将能够准确评估未来的器官损伤。