Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, United States.
World J Gastroenterol. 2011 May 28;17(20):2456-64. doi: 10.3748/wjg.v17.i20.2456.
Alcoholic liver disease (ALD) is characterized by steatosis or fat deposition in the liver and inflammation, which leads to cirrhosis and hepatocellular carcinoma. Induction of target genes without involving changes in DNA sequence seems to contribute greatly to liver injury. Chromatin modifications including alterations in histones and DNA, as well as post-transcriptional changes collectively referred to as epigenetic effects are altered by alcohol. Recent studies have pointed to a significant role for epigenetic mechanisms at the nucleosomal level influencing gene expression and disease outcome in ALD. Specifically, epigenetic alterations by alcohol include histone modifications such as changes in acetylation and phosphorylation, hypomethylation of DNA, and alterations in miRNAs. These modifications can be induced by alcohol-induced oxidative stress that results in altered recruitment of transcriptional machinery and abnormal gene expression. Delineating these mechanisms in initiation and progression of ALD is becoming a major area of interest. This review summarizes key epigenetic mechanisms that are dysregulated by alcohol in the liver. Alterations by alcohol in histone and DNA modifications, enzymes related to histone acetylation such as histone acetyltransferases, histone deacetylases and sirtuins, and methylation enzymes such as DNA methyltransferases are discussed. Chromatin modifications and miRNA alterations that result in immune cell dysfunction contributing to inflammatory cytokine production in ALD is reviewed. Finally, the role of alcohol-mediated oxidative stress in epigenetic regulation in ALD is described. A better understanding of these mechanisms is crucial for designing novel epigenetic based therapies to ameliorate ALD.
酒精性肝病（ALD）的特征是肝脏脂肪沉积和炎症，导致肝硬化和肝细胞癌。不涉及 DNA 序列变化而诱导靶基因似乎对肝损伤有很大贡献。染色质修饰包括组蛋白和 DNA 的改变，以及被统称为表观遗传效应的转录后变化，都会被酒精改变。最近的研究表明，表观遗传机制在核小体水平上对影响 ALD 中基因表达和疾病结果具有重要作用。具体来说，酒精引起的表观遗传改变包括组蛋白修饰，如乙酰化和磷酸化的改变、DNA 的低甲基化以及 microRNA 的改变。这些修饰可以通过酒精诱导的氧化应激引起，导致转录机制的异常募集和异常基因表达。阐明这些在 ALD 的起始和进展中的机制已成为一个主要的研究领域。这篇综述总结了酒精在肝脏中失调的关键表观遗传机制。讨论了酒精对组蛋白和 DNA 修饰、与组蛋白乙酰化相关的酶（如组蛋白乙酰转移酶、组蛋白去乙酰化酶和 sirtuins）以及甲基化酶（如 DNA 甲基转移酶）的改变。综述了导致免疫细胞功能障碍的染色质修饰和 microRNA 改变，从而导致 ALD 中炎症细胞因子的产生。最后，描述了酒精介导的氧化应激在 ALD 中的表观遗传调控中的作用。更好地理解这些机制对于设计新的基于表观遗传的治疗方法来改善 ALD 至关重要。
