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

基本信息

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
项目类别：
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

项目摘要

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.

乙醇代谢产生氧化应激，慢性乙醇暴露改变线粒体功能。现存的主要问题是哪些事件和过程链接酒精引起的线粒体功能障碍和ROS产生到局部和远端组织损害。我们还不知道线粒体如何受到乙醇代谢的破坏和ROS形成，有毒材料的分子身份（IES），也不是其特异性的目标。肝脏的乙醇代谢如何导致周围和远端的损害组织也保持不透明。我们也缺乏倾向的可靠循环标记用于组织损伤。我们最近确定了特定的氧化性磷脂，很容易运输到细胞中，在那里它们插入线粒体膜以启动线粒体依赖性凋亡。现在我们发现这些脂质，脂质炎症介体血小板激活因子（PAF）和独特的羟基化磷脂是在长期摄入乙醇的大鼠循环中，所有这些都增加了。早期结果表明这也发生在人类综合征的早期。因此，这些脂质在循环由乙醇的肝代谢产生的内源性氧化过程的标记。此外，它们本身可能会通过其选择性目标的失调，即通电线粒体。该提案的目的是：1）定义循环的来源，身份和数量脂质氧化产物在动物和人类长期摄入乙醇中循环。 2）确定氧化脂质如何影响线粒体功能，以及是否是否线粒体功能以细胞特异性方式损害。 3）确定是否 PAF乙酰水合酶，一种特异性水解氧化改性的酶磷脂，保护乙醇代谢期间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，但足够直到Diease后期才能获得应计损害进展的标记过程。该项目将验证新型循环脂质作为疾病相关标记，但是，重要的是，由于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。