Role of mitochondrial calcium in the pathogenesis of alcoholic liver disease

线粒体钙在酒精性肝病发病机制中的作用

• 批准号: 8120893
• 负责人: LAWRENCE D GASPERS
• 金额: $ 33.4万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-10 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120893
• 关键词: Acetaldehyde; Acute; Affect; Alcohol abuse; Alcohol consumption; Alcohol-Induced Disorders; Alcoholic Intoxication; Alcoholic Liver Diseases; Alcohols; Animal Feed; Animal Model; Animals; Apoptosis; Apoptotic; Biochemical; Blood; Calcium; Catabolism; Catecholamines; Cell Death; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chronic; Coupled; Cytochromes; Cytosol; DNA-Binding Proteins; Data; Diet; Energy Metabolism; Ethanol; Ethanol toxicity; Figs - dietary; Fluorescence; Hepatocyte; Hormones; Imaging Techniques; Injury; Inositol; Lead; Liquid substance; Liver; Liver diseases; Luciferases; Measures; Mediating; Membrane Potentials; Metabolism; Mitochondria; Mitochondrial Matrix; Mitochondrial Proteins; Modeling; Modification; Molecular; Molecular Biology; Morbidity - disease rate; NADH; Pathogenesis; Pathway interactions; Patients; Peptides; Phosphatidylinositols; Phospholipase C; Physiology; Play; Predisposition; Process; Production; Protein Isoforms; Proteins; Rattus; Reactive Oxygen Species; Role; Signal Pathway; Signal Transduction; Site; Staging; Stimulus; TNF gene; Tissues; Toxic effect; acetaldehyde dehydrogenase; adduct; cell injury; cell type; chronic alcohol ingestion; cytokine; cytotoxic; enzyme activity; feeding; fluorescence imaging; inhibitor/antagonist; insight; mitochondrial dysfunction; mitochondrial membrane; mortality; oxidation; problem drinker; pyridine nucleotide; receptor coupling; research study; response

DESCRIPTION (provided by applicant): Alcohol abuse has deleterious affects on almost every tissue in the body and is a major cause of morbidity and mortality worldwide. The acute actions of alcohol on cellular function are fully reversible whereas long-term alcohol intoxication can lead to irreversible tissue damage. The molecular mechanisms contributing to the onset and progression of irreversible cell injury are still poorly understood. In this application, we propose to investigate the hypothesis that adaptive changes in the phosphoinositide-dependent signaling pathway play a key role in the pathogenesis of alcohol-induced tissue injury. Our preliminary data indicate that feeding rats an ethanol-containing liquid diet (i.e., DeCarli-Lieber) for 60 days enhances the liver' sensitivity to hormones coupled to phospholipase C-¿. The addition of low concentrations of hormones evoked more sustained cytosolic calcium increases in hepatocytes isolated from alcohol-fed animals compared to their pairfed controls. Moreover, cells from alcoholic animals had a larger increase in inositol-1,4,5-trisphosphate (InsP3) formation following low hormone stimulation suggesting that chronic alcohol consumption altered phospholipase C-¿ activity. Normally, cytosolic calcium increases activate mitochondrial physiology to match ATP formation with utilization; however prolonged or inappropriate calcium increases can also lead to matrix calcium overload and mitochondrial dysfunction. Mitochondrial damage is a common feature observed in chronic alcoholic patients and animal models of alcohol abuse. Mitochondrial dysfunction may increase the tissues' susceptibility to other types of injury or apoptotic stimuli. This may be particularly important in chronic alcoholics that have elevated levels of TNFa, a proinflammatory cytokine, which evokes apoptotic cell death in hepatocytes through the mitochondrial-dependent pathway. In this proposal, we will (1) characterize the alcohol-induced alterations in phosphoinositide-dependent signaling pathway, (2) determine the effects of InsP3-dependent calcium increases on mitochondrial calcium levels and energy metabolism in control and chronically ethanol-fed rats and (3) determine the effects Ca2+-moblizing hormones on TNFa-induced apoptosis in hepatocytes from alcohol-fed rats and their pair-fed controls. The proposed studies will provide new insights into the adaptive responses evoked by the sustained presence of ethanol and the associated injurious consequences for the liver.

描述（由申请人提供）：酗酒对身体的几乎每个组织都有有害影响，是全世界发病和死亡的主要原因。酒精对细胞功能的急性作用是完全可逆的，而长期酒精中毒会导致不可逆的组织损伤。导致不可逆细胞损伤发生和进展的分子机制仍知之甚少。在本申请中，我们提出研究这样的假设：磷酸肌醇依赖性信号通路的适应性变化在酒精引起的组织损伤的发病机制中发挥关键作用。我们的初步数据表明，给大鼠喂食含乙醇的流质饮食（即 DeCarli-Lieber）60 天可增强肝脏对与磷脂酶 C-¿ 偶联的激素的敏感性。与成对喂养的对照组相比，添加低浓度的激素会引起从酒精喂养的动物中分离出的肝细胞中更持续的胞质钙增加。此外，在低激素刺激后，来自酗酒动物的细胞中肌醇-1,4,5-三磷酸（InsP3）的形成有更大的增加，这表明长期饮酒改变了磷脂酶C-¿的活性。正常情况下，细胞质钙的增加会激活线粒体生理机能，使 ATP 的形成与利用相匹配；然而，长期或不适当的钙增加也会导致基质钙超载和线粒体功能障碍。线粒体损伤是在慢性酒精患者和酒精滥用动物模型中观察到的一个常见特征。线粒体功能障碍可能会增加组织对其他类型损伤或凋亡刺激的敏感性。这对于 TNFa 水平升高的慢性酗酒者尤其重要，TNFa 是一种促炎细胞因子，可通过线粒体依赖性途径引起肝细胞凋亡。在本提案中，我们将（1）表征酒精诱导的磷酸肌醇依赖性信号通路的改变，（2）确定InsP3依赖性钙增加对对照和长期乙醇喂养大鼠的线粒体钙水平和能量代谢的影响，以及（3）确定Ca2+动员激素对TNFa诱导的肝细胞凋亡的影响 来自酒精喂养的老鼠和配对喂养的对照组。拟议的研究将为乙醇持续存在引起的适应性反应以及相关的肝脏损害后果提供新的见解。