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

过量饮酒是酒精性肝病(ALD)的主要危险因素， 表现为一系列肝脏疾病，包括脂肪变性、脂肪性肝炎、纤维化、肝硬变、 甚至是肝细胞癌。酒精性肝硬变占总数的0.9% 2010年全球死亡人数和47.9%的肝硬变死亡人数。统计数字突出了 酒精对肝脏病理影响的意义。然而，潜在的机制 仍然难以捉摸，而且缺乏治疗方法。为了更好地理解分子 ALD的机制和识别潜在的药物靶点，这位首席研究员(PI)是 研究一种关键的表观遗传调控因子sirtuin 6(SIRT6)，它是一种依赖NAD的组蛋白 脱乙酰酶，它与新陈代谢和炎症有关。SIRT6系统 基因敲除小鼠患有包括肝脏在内的多个器官的慢性炎症，并发展为 进行性肝纤维化。PI的初步研究表明，SIRT6基因的敲除 肝脏中的基因显著加重酒精诱导的肝损伤，使其水平升高 血清天冬氨酸氨基转移酶和纤维化标志物表达增加，提示 SIRT6参与了ALD的发生。我们假设SIRT6起到了防御酒精的作用- 导致肝脏损伤。为了检验这一假设，PI建议执行以下具体操作 目的：1)明确SIRT6在ALD发病中的作用；2)探索SIRT6在ALD发病中的新途径 对酒精性肝损伤的保护作用。总体而言，拟议的研究涉及 这是ALD领域的一个重要问题。人们期望对SIRT6在ALD中的作用有更好的理解 对这一严重疾病的防治工作的发展具有重要意义 疾病。

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.