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: 8709151
• 负责人: LAWRENCE D GASPERS
• 金额: $ 2.62万
• 依托单位: RBHS-NEW JERSEY 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8709151
• 关键词: Role; mitochondrial; calcium; pathogenesis; alcoholic

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（应用程序提供）：酗酒对体内几乎所有组织都有有害影响，这是全球发病率和死亡率的主要原因。酒精对细胞功能的急性作用是完全可逆的，而长期的酒精肠毒可能会导致不可逆转的组织损伤。导致不可逆细胞损伤发作和进展的分子机制仍然很少了解。在此应用中，我们提出了这样的假设，即磷酸肌醇依赖性信号通路的适应性变化在酒精诱导的组织损伤的发病机理中起关键作用。我们的初步数据表明，喂养大鼠含有乙醇的液体饮食（即decarli-lieber）60天，可以增强肝脏对与磷脂酶C-®耦合的激素的敏感性。与配对对照组相比，低浓度的骑马蛋白会引起从酒精喂养动物分离的肝细胞中持续持续的胞质钙的增加。此外，饮酒动物的细胞在低体内刺激后的肌醇1,4,5-三磷酸（INSP3）形成较大，这表明长期饮酒会改变磷脂酶C-®的活性。通常，胞质钙会增加激活线粒体生理，使ATP形成与利用率相匹配。但是，延长或不适当的钙增加也会导致基质钙过载和线粒体功能障碍。线粒体损伤是在慢性酒精患者和酗酒的动物模型中观察到的常见特征。线粒体功能障碍可能会增加组织对其他类型的损伤或凋亡刺激的敏感性。这可能在慢性酗酒者的TNFA水平升高（一种促炎细胞因子）中尤其重要，它通过线粒体依赖性途径唤起肝细胞中的凋亡细胞死亡。 In this proposal, we will (1) characterize the alcohol-induced alterations in phosphoinositiide-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 horrmones on TNFa-induced apoptosis in来自酒精喂养大鼠及其成对对照的肝细胞。拟议的研究将为乙醇的持续存在以及对肝脏的损伤后果所引起的适应性反应提供新的见解。

项目成果

The effect of chronic alcohol consumption on mitochondrial calcium handling in hepatocytes.

• DOI: 10.1042/bcj20160255
• 发表时间: 2016-11-01
• 期刊: The Biochemical journal
• 作者: Wang G;Mémin E;Murali I;Gaspers LD
• 通讯作者: Gaspers LD

Ethanol Disrupts Hormone-Induced Calcium Signaling in Liver.

• DOI: 10.1093/function/zqab002
• 发表时间: 2021
• 期刊: Function (Oxford, England)
• 作者: Gaspers LD;Thomas AP;Hoek JB;Bartlett PJ
• 通讯作者: Bartlett PJ

Hormone-induced calcium oscillations depend on cross-coupling with inositol 1,4,5-trisphosphate oscillations.

• DOI: 10.1016/j.celrep.2014.10.033
• 发表时间: 2014-11-20
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Gaspers LD;Bartlett PJ;Politi A;Burnett P;Metzger W;Johnston J;Joseph SK;Höfer T;Thomas AP
• 通讯作者: Thomas AP