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

Hyeong Geug Kim, Menghao Huang, Yue Xin, Yang Zhang, Xinge Zhang, Gaihong Wang, Sheng Liu, Jun Wan, Ali Reza Ahmadi, Zhaoli Sun, Suthat Liangpunsakul, Xiwen Xiong, X. Dong

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalJournal of Hepatology
DOIs
StateAccepted/In press - Jan 1 2019

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Epigenomics
Oxidative Stress
Alcohols
Liver Diseases
Liver
Wounds and Injuries
Knockout Mice
Inflammation
Ethanol
Transgenic Mice
Transcription Factors
Metals
Genes
Alcoholic Hepatitis
Metallothionein
Chromatin Immunoprecipitation
Luciferases
DNA Repair
NAD
Reactive Oxygen Species

Keywords

  • Alcohol-related liver disease
  • Alcoholic hepatitis
  • Cirrhosis
  • Epigenetic regulation
  • Liver injury
  • Oxidative stress
  • SIRT6
  • Sirtuin

ASJC Scopus subject areas

  • Hepatology

Cite this

The epigenetic regulator SIRT6 protects the liver from alcohol-induced tissue injury by reducing oxidative stress in mice. / Kim, Hyeong Geug; Huang, Menghao; Xin, Yue; Zhang, Yang; Zhang, Xinge; Wang, Gaihong; Liu, Sheng; Wan, Jun; Ahmadi, Ali Reza; Sun, Zhaoli; Liangpunsakul, Suthat; Xiong, Xiwen; Dong, X.

In: Journal of Hepatology, 01.01.2019.

Research output: Contribution to journalArticle

Kim, Hyeong Geug ; Huang, Menghao ; Xin, Yue ; Zhang, Yang ; Zhang, Xinge ; Wang, Gaihong ; Liu, Sheng ; Wan, Jun ; Ahmadi, Ali Reza ; Sun, Zhaoli ; Liangpunsakul, Suthat ; Xiong, Xiwen ; Dong, X. / The epigenetic regulator SIRT6 protects the liver from alcohol-induced tissue injury by reducing oxidative stress in mice. In: Journal of Hepatology. 2019.
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AU - Kim, Hyeong Geug

AU - Huang, Menghao

AU - Xin, Yue

AU - Zhang, Yang

AU - Zhang, Xinge

AU - Wang, Gaihong

AU - Liu, Sheng

AU - Wan, Jun

AU - Ahmadi, Ali Reza

AU - Sun, Zhaoli

AU - Liangpunsakul, Suthat

AU - Xiong, Xiwen

AU - Dong, X.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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KW - Alcoholic hepatitis

KW - Cirrhosis

KW - Epigenetic regulation

KW - Liver injury

KW - Oxidative stress

KW - SIRT6

KW - Sirtuin

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