Dataset Information

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

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.

SUBMITTER: Kim HG

PROVIDER: S-EPMC6801027 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Kim Hyeong Geug HG Huang Menghao M Xin Yue Y Zhang Yang Y Zhang Xinge X Wang Gaihong G Liu Sheng S Wan Jun J Ahmadi Ali Reza AR Sun Zhaoli Z Liangpunsakul Suthat S Xiong Xiwen X Dong Xiaocheng Charlie XC

Journal of hepatology 20190708 5

<h4>Background & aims</h4>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.<h4>Methods</h4>We developed and characterized Sirt6 knockout (KO) and transgenic mouse models that ...[more]

PMID: 31295533

Similar Datasets

Project description:BACKGROUND & AIMS:Sterile inflammation resulting in alcoholic hepatitis (AH) occurs unpredictably after many years of excess alcohol intake. The factors responsible for the development of AH are not known but mitochondrial damage with loss of mitochondrial function are common features. Hcar2 is a G-protein coupled receptor which is activated by ?-hydroxybutyrate (BHB). We aimed to determine the relevance of the BHB-Hcar2 pathway in alcoholic liver disease. METHODS:We tested if loss of BHB production can result in increased liver inflammation. We further tested if BHB supplementation is protective in AH through interaction with Hcar2, and analyzed the immune and cellular basis for protection. RESULTS:Humans with AH have reduced hepatic BHB, and inhibition of BHB production in mice aggravated ethanol-induced AH, with higher plasma alanine aminotransferase levels, increased steatosis and greater neutrophil influx. Conversely supplementation of BHB had the opposite effects with reduced alanine aminotransferase levels, reduced steatosis and neutrophil influx. This therapeutic effect of BHB is dependent on the receptor Hcar2. BHB treatment increased liver Il10 transcripts, and promoted the M2 phenotype of intrahepatic macrophages. BHB also increased the transcriptional level of M2 related genes in vitro bone marrow derived macrophages. This skewing towards M2 related genes is dependent on lower mitochondrial membrane potential (??) induced by BHB. CONCLUSIONS:Collectively, our data shows that BHB production during excess alcohol consumption has an anti-inflammatory and hepatoprotective role through an Hcar2 dependent pathway. This introduces the concept of metabolite-based therapy for AH. LAY SUMMARY:Alcoholic hepatitis is a life-threatening condition with no approved therapy that occurs unexpectedly in people who consume excess alcohol. The liver makes many metabolites, and we demonstrate that loss of one such metabolite ?-hydroxybutyrate occurs in patients with alcoholic hepatitis. This loss can increase alcohol-induced liver injury, and ?-hydroxybutyrate can protect from alcohol-induced liver injury via a receptor on liver macrophages. This opens the possibility of metabolite-based therapy for alcoholic hepatitis.

Project description:Recent reports indicated that mitophagy protects against alcohol-induced liver injury, which helps remove damaged mitochondria to reduce the accumulation of reactive oxygen species (ROS). AMP-activated protein kinase (AMPK) has been recently used in ALD (alcoholic liver disease) and mitochondrial dysfunction research. However, the inner mechanism, whether AMPK can regulate mitophagy in ALD, remains unknown. Here we found that AMPK can significantly reduce alcohol-induced liver injury and enhances hepatocytes' mitophagy level. Next, we identified that AMPK rescued alcohol-induced low expression of UQCRC2 (ubiquinol-cytochrome c reductase core protein 2). Interestingly, UQCRC2 knockdown (KD) treatment causes impaired mitophagy, whereas UQCRC2 overexpression (OE) can significantly increase mitophagy to attenuate liver injury. Also, we identified that AMPK indirectly upregulates UQCRC2 protein level, and RNA-seq, chromatin immunoprecipitation (ChIP) assay, bioinformatics, and luciferase assays helped us understand that AMPK enhanced UQCRC2 gene transcription through activating NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2). Our results demonstrate that AMPK regulating UQCRC2 is a significant mitochondrial event in mitophagy. It identifies a new signaling axis, AMPK-NFE2L2-UQCRC2, in the regulation of mitophagy levels in the liver, suggesting a possible therapeutic strategy to treat ALD.Abbreviations: AAV: AENO-associated virus; ALD: alcoholic liver disease; AMPK: AMP-activated protein kinase; BUN: blood urea nitrogen; H&E: hematoxylin and eosin; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ChIP: chromatin immunoprecipitation assay; CO-IP: co-immunoprecipitation; COPD: chronic obstructive pulmonary disease; EM: electron microscope; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic-pyruvic transaminase; IF: immunofluorescence; IHC: immunohistochemistry; KD: knockdown; MAP1LC3/LC3: microtubule associated protein 1 light chain protein 3; MTDR: MitoTracker Deep Red; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; mtDNA: mitochondrial DNA; MTRC: MitoTracker Red CMXRos; OCR: Oxygen consumption rate; OE: overexpress; PINK1: PTEN induced kinase 1; qRT-PCR: quantitative real-time PCR; ROS: reactive oxygen species; SD: standard deviation; SOD2: superoxide dismutase 2; UQCRC2: ubiquinol-cytochrome c reductase core protein 2; WB: western blot; ΔΨ: mitochondrial membrane potential.

Project description:Alcohol liver disease (ALD) is a liver disease caused by long-term heavy drinking. Glucosamine (GLC) is an amino monosaccharide that plays a very important role in the synthesis of human and animal cartilage. GLC is commonly used in the treatment of mild to moderate osteoarthritis and has good anti-inflammatory and antioxidant properties. In this study, alcoholic injury models were constructed in mice and human normal hepatocyte L02 cells to explore the protective effect and mechanism of GLC on ALD. Mice were given GLC by gavage for 30 days. Liver injury models of both mice and L02 cells were produced by ethanol. Detecting the levels of liver injury biomarkers, lipid metabolism, oxidative stress biomarkers, and inflammatory factors through different reagent kits. Exploring oxidative and inflammatory pathways in mouse liver tissue through Western blot and RT-PCR. The results showed that GLC can significantly inhibit the abnormal increase of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), triglycerides (TG), total cholesterol (TC), very low density lipoprotein (VLDL), low-density lipoprotein cholesterol (LDL-C), and can significantly improve the level of high-density lipoprotein cholesterol (HDL-C). In addition, GLC intervention significantly improved alcohol induced hepatic oxidative stress by reducing the levels of malondialdehyde (MDA) and, increasing the levels of glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) in the liver. Further mechanisms suggest that GLC can inhibit the expression of ethanol metabolism enzyme cytochrome P4502E1 (CYP2E1), activate the antioxidant pathway Keap1/Nrf2/HO-1, down-regulate the phosphorylation of MAPK and NF-κB signaling pathways, and thus reduce the expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). Therefore, GLC may be a significant candidate functional food for attenuating alcohol induced acute liver injury.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets