The epigenetic regulator SIRT6 protects the liver from alcohol-induced tissue injury by reducing oxidative stress in mice

Abstract

As an NAD + -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 alcoholic liver disease (ALD) remains unclear. The aim of this study was to investigate the function and mechanism of SIRT6 in ALD pathogenesis. We developed and characterized Sirt6 knockout (KO) and transgenic (Tg) 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. The Sirt6 KO mice developed severe liver injury manifested by a remarkable increase of oxidative stress and inflammation whereas the Sirt6 Tg 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 anti-oxidative stress, including metallothionein 1 and 2 ( Mt1 and Mt2 ). Mt1/2 genes were down-regulated in the livers of Sirt6 KO mice and alcoholic hepatitis patients. 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 Mtf1 transcriptional activity. Our data suggest that SIRT6 plays a critical protective role against ALD and it may serve as a potential therapeutic target for ALD. 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 liver from the oxidative stress-induced liver injury. Thus, our data suggest that SIRT6 may be a potential therapeutic target for alcohol-related liver disease.