近日，卫生毒理学研究团队在酒精代谢酶调控机制领域取得重要进展。相关研究成果以“A novel mechanism underlying alcohol dehydrogenase expression: hsa-miR-148a-3p promotes ADH4 expression via an AGO1-dependent manner in control and ethanol-exposed hepatic cells”为题，在线发表在期刊Biochemical Pharmacology（IF=4.96，药学1区，DOI: 10.1016/j.bcp.2021.114458）上。
饮酒在许多文化、宗教和社会习俗中非常流行。然而，长期过量饮酒对人体健康有多种危害，酒精性肝炎(AH)是酒精性肝病中最严重的一种。世界卫生组织(WHO)发布的《全球酒精与健康状况报告(2018)》指出，有害饮酒导致的死亡率高于艾滋病、结核病和糖尿病等其他疾病，2016年约有300万人死亡。到目前为止，酗酒在全球范围内是一个日益沉重的负担，并对全球公共健康构成了巨大威胁。虽然酒精对肝脏损伤的影响已经被清楚地记录下来，但目前酒精代谢基因表达的潜在机制研究仍然有限。在肝细胞中，乙醇主要由乙醇脱氢酶(ADH)氧化为乙醛，乙醛由乙醛脱氢酶(ALDH)转化为乙酸。现已知道，ADH和ALDH之间的表达或活性失衡是导致酒精中毒发生和酒精相关组织损伤的关键因素。
本研究发现， miR-148a通过直接与ADH4的编码序列结合，并通过AGO1依赖的方式增加mRNA的稳定性，从而促进ADH4的表达。miR-148a对ADH4的非经典正调控揭示了ADH基因的一种新的调控机制，为阐明ADH基因的表观遗传调控机制提供了新的线索。于典科教授为本文的通讯作者，博士后罗娇和硕士研究生侯宇飞为本文的共同第一作者。上述研究得到国家自然科学基金(81903354,91943301,91743113)、中国博士后科学基金(2020M672008)、国家重点研发计划(2017YFC1600201)、山东省博士后创新项目和青岛市博士后应用研究项目资助。
Alcohol drinking is very popular in many cultural, religious and social practices. However, chronic and excess alcohol drinking has various detrimental effects on human health, including alcoholic hepatitis (AH), the most severe form of alcoholic liver disease. Global status report on alcohol and health (2018) released by World Health Organization (WHO) points out that mortality resulting from harmful use of alcohol is higher than that caused by other diseases such as AIDS, tuberculosis, and diabetes, with about 3 million deaths in 2016. To date, alcohol abuse is a growing burden worldwide and poses a big threat to global public health. While the effects of alcohol on liver injury have been clearly documented, mechanisms underlying the expressions of alcohol-metabolizing genes are currently limited. Principally, alcohol is oxidized to acetaldehyde in hepatic cells by alcohol dehydrogenase (ADH), and acetaldehyde is converted to acetate by aldehyde dehydrogenase (ALDH). It is now known that the expression or activity imbalance between ADH and ALDH is a critical factor contributing to alcoholism development and alcohol-related tissue damage.
In the present study, we showed miR-148a promoted ADH4 expression by directly binding to the coding sequence of ADH4 and increasing the mRNA stability via an AGO1-dependent manner. The non-canonical positive regulation of miR-148a on ADH4 revealed a new regulationary mechanism for ADH genes and provided new clues to elucidate the epigenetic regulationary mechanism of ADH genes.
Dr. Dianke Yu is the corresponding author of the paper. Dr. Jiao Luo and postgraduate students Yufei Hou are the co-first authors. This work was supported by grants from the National Natural Science Foundation of China (81903354, 91943301, and 91743113),China Postdoctoral Science Foundation (2020M672008), National Key R&D Program of China (2017YFC1600201), Postdoctoral Innovation Project of Shandong Province, and the Qingdao Postdoctoral Application Research Project.
