组蛋白去乙酰化酶 SIRT6 通过减少小鼠肝脏中的氧化应激来保护肝脏免受酒精引起的组织损伤。
The epigenetic regulator SIRT6 protects the liver from alcohol-induced tissue injury by reducing oxidative stress in mice.
机构信息
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
出版信息
J Hepatol. 2019 Nov;71(5):960-969. doi: 10.1016/j.jhep.2019.06.019. Epub 2019 Jul 8.
BACKGROUND & AIMS: As a nicotinamide adenine dinucleotide-dependent deacetylase and a key epigenetic regulator, sirtuin 6 (SIRT6) has been implicated in the regulation of metabolism, DNA repair, and inflammation. However, the role of SIRT6 in alcohol-related liver disease (ALD) remains unclear. The aim of this study was to investigate the function and mechanism of SIRT6 in ALD pathogenesis.
METHODS
We developed and characterized Sirt6 knockout (KO) and transgenic mouse models that were treated with either control or ethanol diet. Hepatic steatosis, inflammation, and oxidative stress were analyzed using biochemical and histological methods. Gene regulation was analyzed by luciferase reporter and chromatin immunoprecipitation assays.
RESULTS
The Sirt6 KO mice developed severe liver injury characterized by a remarkable increase of oxidative stress and inflammation, whereas the Sirt6 transgenic mice were protected from ALD via normalization of hepatic lipids, inflammatory response, and oxidative stress. Our molecular analysis has identified a number of novel Sirt6-regulated genes that are involved in antioxidative stress, including metallothionein 1 and 2 (Mt1 and Mt2). Mt1/2 genes were downregulated in the livers of Sirt6 KO mice and patients with alcoholic hepatitis. Overexpression of Mt1 in the liver of Sirt6 KO mice improved ALD by reducing hepatic oxidative stress and inflammation. We also identified a critical link between SIRT6 and metal regulatory transcription factor 1 (Mtf1) via a physical interaction and functional coactivation. Mt1/2 promoter reporter assays showed a strong synergistic effect of SIRT6 on the transcriptional activity of Mtf1.
CONCLUSIONS
Our data suggest that SIRT6 plays a critical protective role against ALD and it may serve as a potential therapeutic target for ALD.
LAY SUMMARY
The liver, the primary organ for ethanol metabolism, can be damaged by the byproducts of ethanol metabolism, including reactive oxygen species. In this study, we have identified a key epigenetic regulator SIRT6 that plays a critical role in protecting the liver from oxidative stress-induced liver injury. Thus, our data suggest that SIRT6 may be a potential therapeutic target for alcohol-related liver disease.
背景与目的
作为烟酰胺腺嘌呤二核苷酸依赖性去乙酰化酶和关键的表观遗传调控因子，Sirtuin 6（SIRT6）参与了代谢、DNA 修复和炎症的调节。然而，SIRT6 在酒精相关肝病（ALD）中的作用尚不清楚。本研究旨在探讨 SIRT6 在 ALD 发病机制中的作用和机制。
方法
我们构建了 Sirt6 敲除（KO）和转基因小鼠模型，并对其进行了对照或乙醇饮食处理。采用生化和组织学方法分析肝脂肪变性、炎症和氧化应激。通过荧光素酶报告和染色质免疫沉淀分析来分析基因调控。
结果
Sirt6 KO 小鼠发生严重的肝损伤，其特征为氧化应激和炎症显著增加，而 Sirt6 转基因小鼠通过肝脂质、炎症反应和氧化应激的正常化而免受 ALD 的影响。我们的分子分析确定了一些新的 Sirt6 调控基因，这些基因参与抗氧化应激，包括金属硫蛋白 1 和 2（Mt1 和 Mt2）。Sirt6 KO 小鼠和酒精性肝炎患者的肝脏中 Mt1/2 基因表达下调。在 Sirt6 KO 小鼠的肝脏中过表达 Mt1 可通过降低肝氧化应激和炎症来改善 ALD。我们还通过物理相互作用和功能共激活发现了 SIRT6 和金属调节转录因子 1（Mtf1）之间的关键联系。Mt1/2 启动子报告基因分析显示 SIRT6 对 Mtf1 的转录活性具有很强的协同作用。
结论
我们的数据表明，SIRT6 在对抗 ALD 中起着关键的保护作用，它可能成为 ALD 的潜在治疗靶点。
要点
肝脏是乙醇代谢的主要器官，乙醇代谢的副产物，包括活性氧，可以损伤肝脏。在这项研究中，我们发现了一种关键的表观遗传调控因子 SIRT6，它在保护肝脏免受氧化应激诱导的肝损伤方面起着关键作用。因此，我们的数据表明，SIRT6 可能是治疗酒精相关肝病的潜在靶点。
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