Hyeong Geug Kim1, Menghao Huang2, Yue Xin3, Yang Zhang1, Xinge Zhang3, Gaihong Wang1, Sheng Liu4, Jun Wan5, Ali Reza Ahmadi6, Zhaoli Sun6, Suthat Liangpunsakul7, Xiwen Xiong8, Xiaocheng Charlie Dong9. 1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. 2. 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. 3. School of Forensic Medicine, Xinxiang Medical University, Xinxiang, Henan 453003, PR China; Xinxiang Key Laboratory of Metabolism and Integrative Physiology, Xinxiang Medical University, Xinxiang, Henan 453003, PR China. 4. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. 5. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Center of Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. 6. Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 7. Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Roudebush Veterans Administration Medical Center, Indianapolis, IN 46202, USA. 8. School of Forensic Medicine, Xinxiang Medical University, Xinxiang, Henan 453003, PR China; Xinxiang Key Laboratory of Metabolism and Integrative Physiology, Xinxiang Medical University, Xinxiang, Henan 453003, PR China. Electronic address: xwxiong@xxmu.edu.cn. 9. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: xcdong@iu.edu.
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.
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 transgenicmouse 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 Sirt6transgenic 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.
Authors: Ashwani K Singal; Ramon Bataller; Joseph Ahn; Patrick S Kamath; Vijay H Shah Journal: Am J Gastroenterol Date: 2018-01-16 Impact factor: 10.864
Authors: Jagannath Misra; Michael J Holmes; Emily T Mirek; Michael Langevin; Hyeong-Geug Kim; Kenneth R Carlson; Malcolm Watford; X Charlie Dong; Tracy G Anthony; Ronald C Wek Journal: Nucleic Acids Res Date: 2021-06-04 Impact factor: 16.971
Authors: Lihua Hao; In Hyuk Bang; Jie Wang; Yuancheng Mao; Jae Do Yang; Soon-Young Na; Jeong Kon Seo; Hueng-Sik Choi; Eun Ju Bae; Byung-Hyun Park Journal: JCI Insight Date: 2020-09-03