Systemic Oxidized Phospholipids in Mitochondrial Dysfunction of Alcoholic Injury

描述(申请人提供)：酒精代谢会产生氧化应激，长期接触酒精会改变线粒体功能。现存的中心问题是，哪些事件和过程将酒精诱导的线粒体功能障碍和ROS的产生与局部和远端组织损伤联系起来。我们还不知道乙醇代谢和ROS的形成是如何破坏线粒体的，有毒物质的分子同一性，也不知道它们的特定靶点。肝脏的乙醇代谢如何导致周围和远端组织的损害也仍然不清楚。我们也缺乏可靠的组织损伤倾向的循环标志物。我们最近发现了特定的氧化碎裂磷脂，它们很容易被转运到细胞内，在那里它们插入线粒体膜，启动线粒体依赖的细胞凋亡。我们现在发现，在长期摄入酒精的大鼠的循环中，这些脂质、脂质炎症介质血小板激活因子(PAF)和独特的羟化磷脂都会增加。早期的结果表明，这也发生在人类综合症的早期。因此，这些脂质是由肝脏乙醇代谢引起的内源性氧化过程的循环标志。此外，它们本身也可能通过对其选择性靶标--被激活的线粒体--的失调而导致近端和远端组织损伤。本申请的目的是1)确定在长期摄入乙醇的动物和人类中循环的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有的方式受损。3)确定PAF乙酰水解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，直到疾病进程的晚期，才有足够的标记物来描述累积损伤的进展。该项目将验证新的循环脂质作为疾病相关标记物的有效性，但重要的是，由于这些相同的脂质会导致组织损伤，我们将能够准确地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.