Systemic Oxidized Phospholipids in Mitochondrial Dysfunction of Alcoholic Injury

描述（由申请人提供）：乙醇代谢会产生氧化应激，慢性乙醇暴露会改变线粒体功能。现有的核心问题是哪些事件和过程将酒精引起的线粒体功能障碍和 ROS 生成与局部和远端组织损伤联系起来。我们尚不知道乙醇代谢和活性氧形成如何损害线粒体，也不知道有毒物质的分子特性，也不知道它们的具体目标。肝脏代谢乙醇如何导致周围和远端组织损伤仍然不透明。我们还缺乏组织损伤倾向的可靠循环标记。我们最近发现了特定的氧化断裂磷脂，它们很容易被转运到细胞中，并插入线粒体膜中以启动线粒体依赖性细胞凋亡。我们现在发现这些脂质、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乙醇的大鼠的循环中都会增加。早期结果表明，这种情况也发生在人类综合症的早期。因此，这些脂质是肝脏乙醇代谢产生的内源性氧化过程的循环标志物。此外，它们本身可能通过其选择性目标、通电线粒体的失调而引起近端和远端组织损伤。该应用的目的是 1) 定义在动物和人类长期摄入乙醇中循环的循环脂质氧化产物的来源、身份和数量。 2) 确定氧化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受到损害。 3) 确定PAF乙酰水解酶（一种特异性水解氧化修饰磷脂的酶）是否在乙醇代谢过程中保护肝细胞的线粒体功能。酒精性肝和组织损伤是一个重要的公共卫生问题，但直到疾病过程的后期才可获得足够的损伤进展标记。该项目将验证新型循环脂质作为疾病相关标记物，但值得注意的是，由于这些相同的脂质会引起组织损伤，因此我们将能够准确评估未来的器官损伤。

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.