Role of ALDH7A1 in Ethanol-Induced Oxidative Damage

ALDH7A1 在乙醇诱导的氧化损伤中的作用

基本信息

批准号：
8150914
负责人：
Chad Nicholas Brocker
金额：
$ 2.23万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2012-05-25
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8150914
关键词：
Alcohol consumption Alcoholic Liver Diseases Alcoholic liver damage Alcohols Aldehydes Anabolism Animals Apoptosis Automobile Driving Betaine Binding Biochemical Biological CYP2E1 gene Carboxylic Acids Cell Culture Techniques Cell Line Cell Survival Cell membrane Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Chronic Control Animal DBA/2 Mouse DNA DNA Damage DNA Methylation Data Development Diet Disease Enzymes Ethanol Ethanol Metabolism Ethanol toxicity Excision Goals Health Heavy Drinking Hepatic Hepatotoxicity Histology Homeostasis Human In Vitro Knock-out Knockout Mice Lipid Peroxidation Liquid substance Liver Mediating Messenger RNA Methionine Methionine Metabolism Pathway Mitochondria Mouse Strains Mus Nucleic Acids Oxidative Stress Pathology Patients Phospholipids Play Polyunsaturated Fatty Acids Process Production Proteins Reactive Oxygen Species Reporting Role S-Adenosylmethionine Small Interfering RNA Supplementation Testing Therapeutic Tissues Transgenic Mice United States Work adduct alcohol exposure aldehyde dehydrogenases cell injury chronic alcohol ingestion cytotoxicity disorder prevention member methyl group mouse model oxidation oxidative damage prevent public health relevance

项目摘要

DESCRIPTION (provided by applicant): A comprehensive understanding of the fundamental mechanisms driving ethanol toxicity augments the development of highly effective, targeted therapies to both prevent and treat health problems caused by excessive alcohol consumption. The long term goal of this study aims to elucidate the protective functions of aldehyde dehydrogenase 7A1 (ALDH7A1) during ethanol-induced oxidative stress. Ethanol metabolism elevates reactive oxygen species triggering lipid peroxidation (LPO) throughout tissues. The oxidation of polyunsaturated fatty acids in cell membranes via LPO generates over two hundred different types of reactive aldehydes. These molecules bind to protein, DNA and other compounds within cells causing enzyme inactivation, DNA damage and impaired cellular homeostasis. Ethanol-induced oxidative stress also impairs methionine metabolism thereby promoting tissue damage through the depletion of S-adenosylmethionine (SAM). SAM is the principle biological methyl donor and required for protein, phospholipid and DNA methylation. In the liver, chronic ethanol consumption both dramatically elevates LPO-derived aldehyde production and significantly depletes SAM pools. The combined effect of these processes damage cells and contribute to alcohol-induced liver damage. Our preliminary data suggests that ALDH7A1 may be a key player in protecting against ethanol-mediated tissue damage. We have shown that ALDH7A1 metabolizes a number of toxic LPO-derived aldehydes. Furthermore, our data indicates ALDH7A1 generates betaine from betaine aldehyde. Betaine is an important osmolyte and methyl-group donor. Supplementation of betaine during chronic ethanol exposure has been shown to decrease oxidative stress and prevent ethanol-induced liver damage by serving as a precursor for SAM biosynthesis. Our working hypothesis is that ALDH7A1 is involved in cellular defense against ethanol induced-hepatotoxicity by metabolizing LPO-derived aldehydes as well as maintaining methionine homeostasis by generating betaine. We will 1) test the hypothesis that ALDH7A1 protects against ethanol-induced oxidative stress in vitro. By manipulating the levels of ALDH7A1 expression in cell culture, we can gain a better understanding of the role it plays during ethanol metabolism. We will also 2) test the hypothesis that ALDH7A1 protects against ethanol-induced oxidative stress using a liver-specific Aldh7a1 knockout mouse. Liver histology, function and damage during chronic ethanol treatment will be studied in mice lacking ALDH7A1 as compared to control animals. The contribution of ALDH7A1 during ethanol metabolism has yet to be determined and the proposed studies intend to expand upon the above mentioned relationships. Results from this study will broaden our understanding of the processes underlying ethanol-induced tissue damage and support the development of effective therapeutic options for patients suffering from alcohol-related diseases. PUBLIC HEALTH RELEVANCE: Aldehyde dehydrogenase 7A1 (ALDH7A1) is enzyme that removes many toxic molecules produced during ethanol metabolism. Recently it was discovered the enzyme also generates betaine which is compound known to prevent ethanol-related pathologies. This long term goal of this project is to elucidate the protective functions of ALDH7A1 during excessive alcohol consumption.

描述（由申请人提供）：对驱动乙醇毒性的基本机制的全面了解有助于开发高效的靶向疗法，以预防和治疗过量饮酒引起的健康问题。本研究的长期目标旨在阐明乙醛脱氢酶 7A1 (ALDH7A1) 在乙醇诱导的氧化应激过程中的保护功能。乙醇代谢会升高活性氧，从而引发整个组织的脂质过氧化（LPO）。细胞膜中的多不饱和脂肪酸通过 LPO 氧化，产生 200 多种不同类型的活性醛。这些分子与细胞内的蛋白质、DNA 和其他化合物结合，导致酶失活、DNA 损伤和细胞稳态受损。乙醇诱导的氧化应激也会损害蛋氨酸代谢，从而通过消耗 S-腺苷蛋氨酸 (SAM) 促进组织损伤。 SAM 是主要的生物甲基供体，是蛋白质、磷脂和 DNA 甲基化所需的。在肝脏中，长期摄入乙醇会显着提高 LPO 衍生的醛的产量，并显着耗尽 SAM 池。这些过程的综合作用会损害细胞并导致酒精引起的肝损伤。我们的初步数据表明 ALDH7A1 可能是防止乙醇介导的组织损伤的关键因素。我们已经证明 ALDH7A1 可以代谢许多有毒的 LPO 衍生醛。此外，我们的数据表明 ALDH7A1 从甜菜碱醛生成甜菜碱。甜菜碱是一种重要的渗透剂和甲基供体。研究表明，在长期接触乙醇期间补充甜菜碱可以作为 SAM 生物合成的前体，从而减少氧化应激并预防乙醇引起的肝损伤。我们的工作假设是，ALDH7A1 通过代谢 LPO 衍生的醛以及通过生成甜菜碱维持蛋氨酸稳态来参与细胞防御乙醇诱导的肝毒性。我们将 1) 测试 ALDH7A1 在体外可防止乙醇诱导的氧化应激的假设。通过控制细胞培养物中 ALDH7A1 的表达水平，我们可以更好地了解它在乙醇代谢过程中所发挥的作用。我们还将 2) 使用肝脏特异性 Aldh7a1 敲除小鼠来测试 ALDH7A1 可以防止乙醇诱导的氧化应激的假设。将在缺乏 ALDH7A1 的小鼠中与对照动物进行比较，研究长期乙醇治疗期间的肝脏组织学、功能和损伤。 ALDH7A1 在乙醇代谢过程中的贡献尚未确定，拟议的研究旨在扩展上述关系。这项研究的结果将拓宽我们对乙醇引起的组织损伤过程的理解，并支持为患有酒精相关疾病的患者开发有效的治疗方案。公共卫生相关性：乙醛脱氢酶 7A1 (ALDH7A1) 是一种酶，可以去除乙醇代谢过程中产生的许多有毒分子。最近发现该酶还产生甜菜碱，甜菜碱是已知可预防乙醇相关病理的化合物。该项目的长期目标是阐明 ALDH7A1 在过量饮酒期间的保护功能。