Systemic Oxidized Phospholipids in Mitochondrial Dysfunction of Alcoholic Injury

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。目前的核心问题是，酒精诱导的线粒体功能障碍和活性氧生成与局部和远端组织损伤之间存在哪些事件和过程。我们还不知道线粒体是如何被乙醇代谢和ROS形成破坏的，也不知道有毒物质的分子特性，也不知道它们的具体目标。肝脏的乙醇代谢如何导致周围和远端组织的损伤也仍然不清楚。我们也缺乏可靠的组织损伤倾向的循环标记。我们最近发现了特定的氧化碎片磷脂，它们很容易被运输到细胞中，在那里它们嵌入线粒体膜，启动线粒体依赖的细胞凋亡。我们现在发现这些脂质，脂质炎症介质血小板活化因子（PAF）和独特的羟基化磷脂在长期摄入乙醇的大鼠循环中都增加了。早期的研究结果表明，这种情况也发生在人类综合症的早期。因此，这些脂质是由肝脏代谢乙醇引起的内源性氧化过程的循环标记物。此外，它们本身也可能通过选择性靶细胞线粒体的失调而诱发近端和远端组织损伤。本应用程序的目的是：1)确定长期摄入乙醇的动物和人体内循环脂质氧化产物的来源、特性和数量。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损。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。酒精性肝脏和组织损伤是一个重大的公共卫生问题，然而，直到疾病过程的后期才有足够的标志物来显示累积损伤的进展。该项目将验证新型循环脂质作为疾病相关标志物，但值得注意的是，由于这些相同的脂质诱导组织损伤，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.