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.

过量饮酒是酒精性肝病（ALD）的主要危险因素， 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， 甚至肝细胞癌。酒精性肝硬化占所有肝硬化的0.9%， 2010年全球死亡人数和肝硬化死亡人数的47.9%。统计数字显示， 酒精对肝脏病理学影响的意义。然而，潜在的机制 仍然难以捉摸，缺乏治疗方法。为了更好地理解 ALD的机制，并确定潜在的药物靶点，这主要研究者（PI）是 研究一种关键的表观遗传调节因子，sirtuin 6（Sirt 6），一种NAD依赖性组蛋白 脱乙酰酶，其与代谢和炎症有关。Sirt 6系统性 基因敲除小鼠在包括肝脏在内的多个器官中遭受慢性炎症， 进行性肝纤维化PI的初步研究表明，敲除Sirt 6 肝脏中的基因显著抑制了酒精诱导的肝损伤， 血清天冬氨酸转氨酶和纤维化标志物表达增加，表明 Sirt 6参与ALD。我们假设Sirt 6的功能是防止酒精- 导致肝损伤。为了检验这一假设，PI建议进行以下具体的 目的：1）明确Sirt 6在ALD发生发展中的作用; 2）探索一种新的Sirt 6通路， 对酒精性肝损伤的保护作用。总的来说，拟议的研究涉及 ALD领域的一个重要问题。希望能更好地了解Sirt 6在ALD中的作用 对预防和治疗这一严重疾病的发展具有重大意义， 疾病