Effects of Ethanol TNF Induced Cytotoxicity

乙醇 TNF 诱导的细胞毒性作用

• 批准号: 7371534
• 负责人: JOHN G PASTORINO
• 金额: $ 25.94万
• 依托单位: UNIV OF MED/DENT NJ-SCH OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7371534
• 关键词: 1-Phosphatidylinositol 3-Kinase; Alcoholic Liver Diseases; Alcohols; Anions; Benzodiazepine Receptor; Cells; Cessation of life; Cholesterol Homeostasis; Cirrhosis; Data; Diazepam Binding Inhibitor; Disease; Endoplasmic Reticulum; Ethanol; Hepatocyte; Injury; Lipids; Liver; Mitochondria; Modification; Pathway interactions; Peripheral; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Phosphorylation; Play; Predisposition; Proteins; Resistance; Role; Signal Pathway; Steatohepatitis; Stress; Structure; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Voltage-Dependent Anion Channel; Work; adiponectin; alcohol effect; alcohol exposure; cytotoxicity; human TNF protein; lipid biosynthesis; voltage

DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) constitutes a spectrum of disorders in liver structure and function. The alterations in ALD are broadly categorized into alcohol induced steatosis, steatohepatitis and cirrhosis. Tumor necrosis factor (TNF) has been shown to play a critical role in the progression of ALD, partly through it ability to bring about the injury and death of hepatocytes. In the preceding period of support we have uncovered that hepatocytes exposed to ethanol display an increased sensitivity to TNF induced cytotoxicity and that this is driven by an enhanced susceptibility of the mitochondria to injury, which in turn is exploited by alterations in signaling pathways elicited by TNF in ethanol exposed cells. In the present application we intend to both narrow and broaden the scope of our studies. Firstly, we propose that modifications to hepatocyte lipogenesis contribute to the increased vulnerability to TNF induced damage that characterizes the mitochondria of ethanol exposed cells. Specifically, increased expression of acyl CoA binding protein (ACBP) and the peripheral benzodiazepine receptor (PBR) in ethanol exposed cells, proteins involved in lipid and cholesterol metabolism, establish an enhanced susceptibility of the mitochondria to TNF induced damage. Also, derangements of the PI3-kinase/Akt pathway brought about by ethanol exposure results in phosphorylation of the voltage dependent anion carrier (VDAC), with detrimental consequences for mitochondrial function and resistance to injury. The preliminary data also reveal that the alterations imposed on mitochondria by ethanol exposure may mitigate the beneficial effects of adiponectin against TNF induced cytotoxicity, potentially by impeding adiponectin induced activation of the AMPK pathway. The working hypothesis for this proposal is that the derangement of lipogenesis triggered by ethanol exposure causes alterations in mitochondrial function, particularly through an increased expression of acyl CoA binding protein, the peripheral benzodiazepine receptor, phosphorylation of the voltage dependent anion carrier (VDAC) and endoplasmic reticulum stress, all of which render the mitochondria and cell more sensitive to TNF induced injury. Moreover these effects of ethanol can be ameliorated by activation of AMPK.

描述（由申请人提供）：酒精性肝病（ALD）构成了肝脏结构和功能的各种疾病。 ALD的变化大致分为酒精诱导的脂肪变性，脂肪性肝炎和肝硬化。肿瘤坏死因子（TNF）已被证明在ALD的发展中起着至关重要的作用，部分是通过IT造成肝细胞损伤和死亡的能力。在前面的支持阶段，我们发现了暴露于乙醇的肝细胞对TNF诱导的细胞毒性的敏感性提高，并且这是由于线粒体对受伤的易感性增强所致，这又是由TNF在TNF中受到的信号传播的变化而利用的，这又受到TNF在乙醇中的乙醇曝光细胞的变化而利用。在本应用中，我们打算狭窄和扩大我们的研究范围。首先，我们建议对肝细胞脂肪生成的修饰有助于增加TNF诱导损伤的脆弱性，而TNF造成的损伤表征了乙醇暴露的细胞的线粒体。具体而言，在乙醇暴露细胞中，酰基CoA结合蛋白（ACBP）和外周二氮卓受体（PBR）的表达增加，参与脂质和胆固醇代谢的蛋白质增强了线粒体对TNF诱导损伤的敏感性。同样，乙醇暴露带来的PI3-激酶/AKT途径的扰动导致电压依赖性阴离子载体（VDAC）的磷酸化，对线粒体功能和对损伤的抗性产生了不利的后果。初步数据还表明，乙醇暴露对线粒体施加的改变可能会减轻脂联素对TNF诱导的细胞毒性的有益作用，这可能通过阻碍脂联素诱导的AMPK途径激活。该提案的工作假设是，乙醇暴露引起的脂肪生成的危险会导致线粒体功能的改变，特别是通过增加酰基COA结合蛋白的表达，苯并二氮二氮二氮化受体的表达增加，是电压依赖性载体（VDAC）的磷酸化（VDAC）的磷酸化（VDAC）的磷酸化（VDAC）磷酸化磷酸化（VDAC）和胚胎的磷酸化。对TNF诱导损伤更敏感。此外，通过AMPK的激活可以改善乙醇的这些作用。