Role of sirtuin 6 in the protection of liver from the alcohol-induced injury

Sirtuin 6在保护肝脏免受酒精损伤中的作用

• 批准号: 9244917
• 负责人: X Charlie Dong
• 金额: $ 22.43万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-20 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244917
• 关键词: Address; Alcoholic Fatty Liver; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcoholic liver damage; Alcohols; Animal Model; Aspartate Transaminase; Biochemical; CCL2 gene; Cell Death; Cessation of life; ChIP-seq; Characteristics; Cholesterol; Chronic; Cirrhosis; Data; Development; Diet; Disease; Drug Targeting; Epigenetic Process; Ethanol; Extracellular Matrix; Fatty Liver; Fibrosis; Free Radical Scavengers; Gene Expression; Gene Targeting; Genes; Genetic study; Genomics; Gluconeogenesis; Glycolysis; Health; Heavy Drinking; Hepatic; Hepatocyte; Histone Deacetylase; Homeostasis; Human; Hypoglycemia; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-6; Knock-out; Knockout Mice; Knowledge; Life; Lipids; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Metabolic; Metabolism; Metallothionein I; Metallothionein II; Mission; Molecular; Monocyte Chemoattractant Protein-1; Mus; Organ; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Physiological; Play; Prevention; Primary carcinoma of the liver cells; Principal Investigator; Public Health; Regulation; Reporting; Research; Risk Factors; Role; Serum; Sirtuins; Skeletal Muscle; Steatohepatitis; Testing; Therapeutic; Tissues; Transgenic Mice; Triglycerides; United States National Institutes of Health; alcohol abuse therapy; alcohol effect; biological adaptation to stress; burden of illness; genome-wide; glucose uptake; human disease; liver injury; mortality; mouse model; new therapeutic target; next generation; novel; premature; problem drinker

Excessive alcohol consumption is a major risk factor for alcoholic liver disease (ALD), which manifests a spectrum of liver disorders including steatosis, steatohepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. Alcohol related liver cirrhosis accounted for 0.9% of all global deaths and 47.9% of liver cirrhosis mortalities in 2010. The statistical numbers highlight the significance of alcohol effects on the liver pathology. However, the underlying mechanisms are still elusive and therapeutic treatments are lacking. To better understand the molecular mechanisms of ALD and identify potential drug targets, this principal investigator (PI) is investigating a critical epigenetic regulator, sirtuin 6 (Sirt6), an NAD-dependent histone deacetylase, which has been implicated in metabolism and inflammation. Sirt6 systemic knockout mice suffer chronic inflammation in multiple organs including the liver and develop progressive hepatic fibrosis. The PI's preliminary study has revealed that knockout of the Sirt6 gene in the liver significantly worsens the alcohol-induced liver injury with elevated levels of serum aspartate aminotransferase and increased expression of fibrosis markers, suggesting that Sirt6 is involved in ALD. We hypothesize that Sirt6 functions as a safeguard against the alcohol- induced liver damage. To test this hypothesis, the PI proposes to carry out the following specific aims: 1) Define the role of Sirt6 in the development of ALD; 2) Explore a novel Sirt6 pathway in the protection against the alcohol-induced liver injury. Overall, the proposed research addresses an important problem in the ALD field. Better understanding of the role of Sirt6 in ALD is expected to have significant implications for the development of prevention and treatment of this serious disease.

过度饮酒是酒精性肝病（ALD）的主要危险因素，这是 表现出一系列肝脏疾病，包括脂肪变性，脂肪性肝炎，纤维化，肝硬化， 甚至是肝细胞癌。与酒精相关的肝肝硬化占所有肝脏的0.9％ 2010年全球死亡和47.9％的肝硬化死亡率。统计数字突出显示 酒精对肝脏病理的影响。但是，基本机制 仍然难以捉摸，缺乏治疗性治疗。更好地了解分子 ALD的机制并确定潜在的药物靶标，该主要研究者（PI）为 研究临界表观遗传调节剂Sirtuin 6（SIRT6），NAD依赖性组蛋白 脱乙酰基酶，与代谢和炎症有关。 SIRT6系统 敲除小鼠在包括肝脏在内的多个器官中患有慢性炎症并发育 进行性肝纤维化。 PI的初步研究表明，SIRT的淘汰赛6 肝脏中的基因显着恶化酒精诱导的肝损伤，水平升高 血清天冬氨酸氨基转移酶和纤维化标记的表达增加，表明 SIRT6参与了ALD。我们假设SIRT6可以作为防止酒精的保障 诱发肝损害。为了检验这一假设，PI建议执行以下特定 目的：1）定义SIRT6在ALD发展中的作用； 2）在 防止酒精引起的肝损伤的保护。总体而言，拟议的研究讲话 ALD领域的一个重要问题。可以更好地理解SIRT6在ALD中的作用 对这种严重的预防和治疗产生重大影响 疾病。