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: 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
• 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

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和慢性乙醇暴露改变

项目成果

Platelet-activating factor receptor affects food intake and body weight.

血小板激活因子受体会影响食物摄入和体重。

• DOI: 10.1016/j.gendis.2015.06.002
• 发表时间: 2015-09
• 期刊: Genes & diseases
• 影响因子: 6.8
• 作者: Li W;McIntyre TM
• 通讯作者: McIntyre TM

Myeloperoxidase formation of PAF receptor ligands induces PAF receptor-dependent kidney injury during ethanol consumption.

• DOI: 10.1016/j.freeradbiomed.2015.05.020
• 发表时间: 2015-09
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Latchoumycandane C;Nagy LE;McIntyre TM
• 通讯作者: McIntyre TM