Role of Mitochondria in the Regulation of Iron metabolism by Alcohol

线粒体在酒精调节铁代谢中的作用

基本信息

批准号：
7694325
负责人：
Duygu Dee Dee Harrison-Findik
金额：
$ 33.41万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7694325
关键词：
ARNT gene ATP Synthesis Pathway Adenine Nucleotides Alcoholic Liver Diseases Alcohols Animal Model Animals Antioxidants Apoptosis Apoptotic CYP2E1 gene DNA DNA Binding Data Dimerization Duodenum Electron Transport Enzymes Ethanol Exhibits Ferritin Generations Genetic Transcription Hepatic Hepatocyte Hepatology Histology Homeostasis Hypoxia Injury Intestines Iron Iron Overload Knowledge Kupffer Cells Lesion Liver Manganese Superoxide Dismutase Mediating Mitochondria Modification Molecular Oxidation-Reduction Oxidative Stress Pathway interactions Patients Peptides Play Production Protein Biosynthesis Proteins Reactive Oxygen Species Regulation Respiratory Chain Role Stimulus Structure System Transgenic Mice Triglycerides Tumor Necrosis Factor-alpha alcohol effect catalase cytochrome c oxidase cytokine factor C glutathione peroxidase hepatoma cell hepcidin human TNF protein hypoxia inducible factor 1 in vitro Model in vivo in vivo Model iron metabolism macrophage mouse model transcription factor

项目摘要

DESCRIPTION (provided by applicant): Mitochondria are critical in iron metabolism and play a role in alcohol-induced liver injury. Alcohol alters mitochondrial function and leads to oxidative stress. We have demonstrated that alcohol-induced oxidative stress down-regulates hepcidin transcription without causing changes in liver histology or an increase in triglycerides. Hepcidin is a circulatory peptide synthesized in the liver. It plays a central role in iron homeostasis by regulating both intestinal and reticulo-endothelial iron transport. Accordingly, alcohol-treated animals exhibited an increase in the expression of iron transporters in the duodenum and the iron storage protein, ferritin in the liver. Alcohol also rendered hepcidin synthesis in the liver insensitive to body iron levels. It is noteworthy, that hepcidin protects the body from iron overload by inhibiting iron transport. Thus, alcohol may compromise this protective mechanism of hepcidin, which may have implications for alcoholic liver disease (ALD). Of note, ALD patients and animal models of ALD display iron overload but the underlying mechanisms are unclear. Our findings suggest that the deregulation of hepcidin synthesis in the liver may be one of the underlying mechanisms of iron overload observed in ALD. Treatment with antioxidants abolished the effect of alcohol on hepcidin expression. Multiple pathways play a role in alcohol-induced oxidative stress, including activation of Kupffer cells, CYP2E1 enzyme and changes to mitochondrial function. Our preliminary results exclude a role for Kupffer cells, TNF alpha cytokine and CYP2E1 in the regulation of hepcidin expression by alcohol-mediated oxidative stress in the liver. Mitochondria also are involved in alcohol-mediated oxidative stress. Alcohol induces lesions in the proteins of the electron transport chain, and reduces ATP/ADP translocation and ATP synthesis in the mitochondria. Our preliminary results suggest a role for mitochondria in the regulation of hepcidin expression. Inhibition of DNA and protein synthesis in the mitochondria caused a significant decrease in hepcidin expression in plain HepG2 hepatoma cells. Mitochondria play a key role in apoptosis and alcohol-mediated changes in mitochondria induce apoptotic stimuli. However, the role of apoptosis in the regulation of hepcidin expression is unknown. Our preliminary findings demonstrate that Fas-mediated apoptosis down-regulates hepcidin expression in the liver. The objective of this application is to identify the molecular mechanisms whereby mitochondria regulate liver hepcidin expression and iron metabolism by alcohol. Our central hypothesis is that ethanol-induced modifications of mitochondrial structure and function play a key role in the regulation of hepcidin transcription by alcohol. We will employ transgenic mouse models deficient in mitochondrial antioxidant enzymes, adenine nucleotide transport, cytochrome c oxidase activity or the dimerization of hypoxia-inducible transcription factors to study the regulation of hepcidin transcription by alcohol-mediated oxidative stress. The knowledge obtained from these studies, characterizing the pivotal role of mitochondria, will enable us to determine the mechanisms of liver injury caused by iron and alcohol in patients with ALD.

描述（由申请人提供）：线粒体在铁代谢中至关重要，并且在酒精引起的肝损伤中发挥作用。酒精会改变线粒体功能并导致氧化应激。我们已经证明，酒精诱导的氧化应激会下调铁调素转录，而不会引起肝脏组织学的变化或甘油三酯的增加。铁调素是一种在肝脏中合成的循环肽。它通过调节肠道和网状内皮铁转运在铁稳态中发挥核心作用。因此，酒精处理的动物表现出十二指肠中铁转运蛋白和肝脏中铁储存蛋白铁蛋白表达的增加。酒精还会使肝脏中铁调素的合成对体内铁水平不敏感。值得注意的是，铁调素通过抑制铁转运来保护身体免受铁过载的影响。因此，酒精可能会损害铁调素的这种保护机制，这可能对酒精性肝病（ALD）有影响。值得注意的是，ALD 患者和 ALD 动物模型表现出铁超载，但潜在机制尚不清楚。我们的研究结果表明，肝脏中铁调素合成的失调可能是 ALD 中观察到的铁超载的潜在机制之一。用抗氧化剂治疗消除了酒精对铁调素表达的影响。多种途径在酒精诱导的氧化应激中发挥作用，包括库普弗细胞的激活、CYP2E1 酶和线粒体功能的变化。我们的初步结果排除了 Kupffer 细胞、TNF α 细胞因子和 CYP2E1 在酒精介导的肝脏氧化应激调节铁调素表达中的作用。线粒体也参与酒精介导的氧化应激。酒精会引起电子传递链蛋白质的损伤，并减少线粒体中 ATP/ADP 易位和 ATP 合成。我们的初步结果表明线粒体在铁调素表达的调节中发挥作用。线粒体中 DNA 和蛋白质合成的抑制导致普通 HepG2 肝癌细胞中铁调素表达显着下降。线粒体在细胞凋亡中起着关键作用，酒精介导的线粒体变化会诱导细胞凋亡刺激。然而，细胞凋亡在铁调素表达调节中的作用尚不清楚。我们的初步研究结果表明，Fas 介导的细胞凋亡下调肝脏中铁调素的表达。本申请的目的是确定线粒体通过酒精调节肝脏铁调素表达和铁代谢的分子机制。我们的中心假设是乙醇诱导的线粒体结构和功能的改变在酒精调节铁调素转录中发挥关键作用。我们将采用线粒体抗氧化酶、腺嘌呤核苷酸转运、细胞色素c氧化酶活性或缺氧诱导转录因子二聚化缺陷的转基因小鼠模型来研究酒精介导的氧化应激对铁调素转录的调节。从这些研究中获得的知识，表征了线粒体的关键作用，将使我们能够确定铁和酒精对 ALD 患者造成肝损伤的机制。