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Effects of Ethanol TNF Induced Cytotoxicity

乙醇 TNF 诱导的细胞毒性作用

基本信息

批准号：
8812122
负责人：
JOHN G PASTORINO
金额：
$ 24.68万
依托单位：
ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8812122
关键词：
Effects Ethanol TNF Induced Cytotoxicity

项目摘要

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）构成肝脏结构和功能的一系列疾病。 ALD的改变大致分为酒精引起的脂肪变性、脂肪性肝炎和肝硬化。肿瘤坏死因子 (TNF) 已被证明在 ALD 的进展中发挥着关键作用，部分原因是它能够导致肝细胞损伤和死亡。在前期的支持中，我们发现暴露于乙醇的肝细胞对 TNF 诱导的细胞毒性的敏感性增加，这是由线粒体对损伤的敏感性增强所驱动的，而线粒体对损伤的敏感性增强，而线粒体对损伤的敏感性又被暴露于乙醇的细胞中 TNF 引起的信号通路的改变所利用。在本申请中，我们打算缩小和扩大我们的研究范围。首先，我们提出，肝细胞脂肪生成的改变导致对 TNF 诱导的损伤的脆弱性增加，这是乙醇暴露细胞线粒体的特征。具体而言，乙醇暴露细胞中酰基辅酶A结合蛋白（ACBP）和外周苯二氮卓受体（PBR）的表达增加，这些蛋白质参与脂质和胆固醇代谢，从而增强了线粒体对TNF诱导损伤的敏感性。此外，乙醇暴露引起的 PI3 激酶/Akt 通路紊乱会导致电压依赖性阴离子载体 (VDAC) 磷酸化，对线粒体功能和抗损伤能力产生不利影响。初步数据还表明，乙醇暴露对线粒体造成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，这可能是通过阻止脂联素诱导的 AMPK 通路激活来实现的。该提议的工作假设是，乙醇暴露引发的脂肪生成紊乱会导致线粒体功能的改变，特别是通过酰基辅酶A结合蛋白、外周苯二氮卓受体的表达增加、电压依赖性阴离子载体（VDAC）的磷酸化和内质网应激，所有这些都会使线粒体和细胞对 TNF 引起的损伤更敏感。此外，乙醇的这些影响可以通过激活 AMPK 来改善。