Homocysteine and Alcoholic Liver Disease

同型半胱氨酸和酒精性肝病

• 批准号: 7649068
• 负责人: Donald Weldon Jacobsen
• 金额: $ 39.25万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7649068
• 关键词: Address; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; Alcoholism; Alcohols; Apoptosis; Biological Assay; Blood; Carbon; Cells; Chronic; Cirrhosis; Clinical; Cytochrome P-450 CYP2E1; Data; Detection; Disease Progression; Endoplasmic Reticulum; Enzyme-Linked Immunosorbent Assay; Enzymes; Ethanol; Ethanol toxicity; Fluorescence; Functional disorder; Future; Generations; Hepatocyte; High Pressure Liquid Chromatography; Homocysteine; Homocystine; Human; Hyperhomocysteinemia; Immunoprecipitation; Individual; Injury; Lead; Liver; Mediating; Metallothionein; Methionine; Modeling; Molecular; Molecular Chaperones; Molecular Target; Morbidity - disease rate; Organ; Oxidative Stress; Oxidative Stress Induction; Pathway Analysis; Pathway interactions; Patients; Process; Production; Proteins; Proteome; Proteomics; Protocols documentation; Public Health; Rattus; Reactive Oxygen Species; Research; Role; Sodium Dodecyl Sulfate-PAGE; Staging; Steatohepatitis; Testing; Therapeutic; Time; Tissues; Western Blotting; alcohol research; design; economic impact; endoplasmic reticulum stress; feeding; in vivo; insight; mRNA Expression; mortality; novel; novel therapeutic intervention; public health relevance; response

DESCRIPTION (provided by applicant): The public health issues, economic impact and human suffering associated with alcohol abuse are staggering. Although alcohol-related research has been on-going for decades, there are many unanswered questions concerning mechanisms of alcohol-induced tissue injury. Elevated blood homocysteine (hyperhomocysteinemia) is strongly associated with chronic alcoholism. However, the molecular mechanism of elevated homocysteine in alcohol abusers is largely unknown. Of greater importance is the pathological impact and clinical consequences of hyperhomocysteinemia in these individuals. This proposal will provide novel information on the role of methionine synthase (MS) in alcohol-associated hyperhomocysteinemia, homocysteine-induced oxidative and endoplasmic reticulum (ER) stress in models of alcoholic liver disease (ALD), and changes in the one-carbon proteome and metabolome of alcohol-treated cells and liver. The central hypotheses that drive this project are: 1) alcohol-induced oxidative stress in the liver will lead to the inactivation of B12-dependent MS; 2) impaired remethylation of homocysteine results in elevated intracellular homocysteine and hyperhomocysteinemia; 3) molecular targeting of specific intracellular proteins by homocysteine causes enhanced production of reactive oxygen species (ROS), ER stress, and apoptosis; and, 4) the one-carbon proteome and metabolome of the liver is substantially altered in ALD. The specific aims of this project are: 1. to determine the mechanism of inactivation of B12-dependent MS in alcohol-treated cells in culture and in livers from ethanol-fed rats; 2. to establish the role that molecular targeting of specific proteins by L-homocysteine has in the generation of oxidative stress and in the induction of ER stress in alcohol-treated cells and rats; and, 3. to determine whether the decreased SAM/SAH ratio that accompanies ALD is (a) a direct result of alcohol or its metabolites on the levels and/or activities of the methionine cycle enzymes, or (b) an indirect result of the hyperhomocysteinemia that accompanies increased alcohol consumption. These hypotheses will be tested at the cellular level using cultured alcohol-treated or untreated HepG2 E47 and C34 cells and in vivo using livers from rats on the Lieber-DeCarli ethanol feeding model and pair-fed controls. The mechanistic insight gained from this proposal may be useful for establishing novel therapeutic interventions in the treatment of alcoholic liver disease. PUBLIC HEALTH RELEVANCE: The public health issues, economic impact and human suffering associated with alcohol abuse are staggering. Elevated blood homocysteine (hyperhomocysteinemia) is strongly associated with chronic alcoholism. However, the molecular cause of elevated homocysteine and its role in mediating tissue injury in alcoholism is largely unknown. This proposal will provide mechanistic insight on the cause of hyperhomocysteinemia and its deleterious effects to tissues in chronic alcohol abuse.

描述（由申请人提供）：与酒精滥用有关的公共卫生问题、经济影响和人类痛苦是惊人的。尽管与酒精相关的研究已经进行了几十年，但关于酒精诱导的组织损伤机制仍有许多未解之谜。血同型半胱氨酸升高（高同型半胱氨酸血症）与慢性酒精中毒密切相关。然而，酗酒者同型半胱氨酸升高的分子机制在很大程度上是未知的。更重要的是高同型半胱氨酸血症对这些个体的病理影响和临床后果。该提案将提供关于蛋氨酸合成酶（MS）在酒精性肝病（ALD）模型中酒精相关高同型半胱氨酸血症、同型半胱氨酸诱导的氧化和内质网（ER）应激中的作用以及酒精处理细胞和肝脏的单碳蛋白质组和代谢组变化的新信息。推动该项目的核心假设是：1)肝脏中酒精诱导的氧化应激将导致b12依赖性MS失活；2)同型半胱氨酸再甲基化受损导致细胞内同型半胱氨酸升高和高同型半胱氨酸血症；3)同型半胱氨酸对细胞内特定蛋白的分子靶向导致活性氧（ROS）的产生增加、内质网应激和细胞凋亡；4)肝脏的单碳蛋白质组和代谢组在ALD中发生了实质性的改变。本项目的具体目标是：1。确定酒精处理的培养细胞和乙醇喂养大鼠肝脏中b12依赖性MS失活的机制；2. 在酒精处理的细胞和大鼠中，确定l-同型半胱氨酸对特定蛋白质的分子靶向在氧化应激的产生和内质网应激的诱导中的作用；, 3。确定伴有ALD的SAM/SAH比率下降是(a)酒精或其代谢物对蛋氨酸循环酶水平和/或活性的直接结果，还是(b)伴随饮酒增加的高同型半胱氨酸血症的间接结果。这些假设将在细胞水平上通过培养的酒精处理或未处理的HepG2 E47和C34细胞以及Lieber-DeCarli乙醇喂养模型和成对喂养对照组的大鼠肝脏进行测试。从这一建议中获得的机制见解可能有助于建立治疗酒精性肝病的新型治疗干预措施。公共卫生相关性：与酗酒有关的公共卫生问题、经济影响和人类痛苦令人震惊。血同型半胱氨酸升高（高同型半胱氨酸血症）与慢性酒精中毒密切相关。然而，同型半胱氨酸升高的分子原因及其在酒精中毒中介导组织损伤的作用在很大程度上是未知的。这一建议将提供高同型半胱氨酸血症的原因及其对慢性酒精滥用组织的有害影响的机制见解。