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

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

doi:10.1016/j.jhep.2019.06.019

Cited by 103 publications

(79 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Sirt6 is widely associated with in a variety of disease including ischemia/reperfusion and alcoholic hepatic injury [17,33], cardiovascular disease [34], kidney disease [35] and hepatocellular carcinoma [36]. Given the important role of the Sirtuin family in regulating biliary epithelial cell proliferation and bile acid metabolism [14,15], we hypothesized that Sirt6 might play an important role in regulating bile acid-induced apoptosis of biliary epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Sirt6 opposes glycochenodeoxycholate-induced apoptosis of biliary epithelial cells through the AMPK/PGC-1α pathway

Chen

et al. 2020

Cell Biosci

View full text Add to dashboard Cite

Background: Induction of biliary epithelial cell apoptosis by toxic bile acids is involved in the development of cholestatic disease, but the underlying molecular mechanism is not clear. The purpose of this study was to investigate the molecular mechanisms involved in Sirt6 protection against the apoptosis of human intrahepatic biliary epithelial cells (HiBEC) induced by the bile acid glycochenodeoxycholate (GCDC). Results: Sirt6 was either overexpressed or knocked down in HiBEC, with or without GCDC pretreatment. The CCK-8 assay was used to assess cell viability and, Hoechst 33258 staining was used to determine apoptotic rate. Mitochondrial DNA (mtDNA) copy number, malondialdehyde (MDA) and reactive oxygen species (ROS) production were detected to evaluate the severity of the mitochondrial dysfunction and oxidative stress. The mRNA and protein levels of PGC-1α, Nrf1, and Nrf2 were analyzed using RT-qPCR and western blot assay. The results showed that Sirt6 opposed GCDC-induced apoptosis in HiBEC via up-regulating PGC-1α expression and stabilizing mtDNA. We used agonists and inhibitors of AMPK to demonstrate that Sirt6 increased PGC-1α expression through the AMPK pathway whereas GCDC had the opposite effect. Finally, western blot, luciferase assay, and co-immunoprecipitation were used to describe a direct interaction and acetylation modification of PGC-1α by Sirt6. Conclusion: Our data illuminated that Sirt6 ameliorated GCDC-induced HiBEC apoptosis by upregulating PGC-1α expression through the AMPK pathway and its deacetylation effect.

show abstract

Section: Discussionmentioning

confidence: 99%

Sirt6 opposes glycochenodeoxycholate-induced apoptosis of biliary epithelial cells through the AMPK/PGC-1α pathway

Chen

et al. 2020

Cell Biosci

View full text Add to dashboard Cite

show abstract

“…Currently, it is known that epigenetic modifications of liver fibrosis‐related genes in liver fibrosis development . Epigenetic provides to a heritable modulation in gene expression that does not alter the DNA itself . Epigenetic influences generally refer to aberrant DNA methylation and non‐coding RNA (ncRNA) modifications .…”

Section: Introductionmentioning

confidence: 99%

“…[4][5][6] Epigenetic provides to a heritable modulation in gene expression that does not alter the DNA itself. 7,8 Epigenetic influences generally refer to aberrant DNA methylation and non-coding RNA (ncRNA) modifications. 9,10 With regard to the latter, de novo DNA methylation activity catalysed by DNA methyltransferase 3A (DNMT3A) is methylated by addition of transfer methyl groups to the C-5 position in the cytosine ring.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic silencing of LncRNA ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway

Yang

Zhang

et al. 2020

J Cellular Molecular Medi

View full text Add to dashboard Cite

Long non‐coding RNAs (LncRNAs) and DNA methylation are important epigenetic mark play a key role in liver fibrosis. Currently, how DNA methylation and LncRNAs control the hepatic stellate cell (HSC) activation and fibrosis has not yet been fully characterized. Here, we explored the role of antisense non‐coding RNA in the INK4 locus (ANRIL) and DNA methylation in HSC activation and fibrosis. The expression levels of DNA methyltransferases 3A (DNMT3A), ANRIL, α‐Smooth muscle actin (α‐SMA), Type I collagen (Col1A1), adenosine monophosphate‐activated protein kinase (AMPK) and p‐AMPK in rat and human liver fibrosis were detected by immunohistochemistry, qRT‐PCR and Western blotting. Liver tissue histomorphology was examined by haematoxylin and eosin (H&E), Sirius red and Masson staining. HSC was transfected with DNMT3A‐siRNA, over‐expressing ANRIL and down‐regulating ANRIL. Moreover, cell proliferation ability was examined by CCK‐8, MTT and cell cycle assay. Here, our study demonstrated that ANRIL was significantly decreased in activated HSC and liver fibrosis tissues, while Col1A1, α‐SMA and DNMT3A were significantly increased in activated HSC and liver fibrosis tissues. Further, we found that down‐regulating DNMT3A expression leads to inhibition of HSC activation. Reduction in DNMT3A elevated ANRIL expression in activated HSC. Furthermore, we performed the over expression ANRIL suppresses HSC activation and AMPK signalling pathways. In sum, our study found that epigenetic DNMT3A silencing of ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway. Targeting epigenetic modulators DNMT3A and ANRIL, and offer a novel approach for liver fibrosis therapy.

show abstract

“…Additionally, the gut microbiota plays an important role in both nonalcoholic fatty liver disease and alcohol-related liver disease [ 25 ]. Alcohol may affect glucose metabolism in the liver by downregulating gluconeogenesis or changing hepatic lipids, inflammatory response, and oxidative stress by inducing steatosis [ 26 , 27 ]. It may also affect gut microbiota diversity and interfere with the protective effect of beneficial bacteria [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Serum Glycated Albumin Levels Are Affected by Alcohol in Men of the Jinuo Ethnic Group in China

Zhu

Hou

et al. 2021

Canadian Journal of Infectious Diseases and Medical Microbiolog

View full text Add to dashboard Cite

Aim. To investigate the effects of alcohol on serum glycated albumin (GA) levels in Chinese men. Methods. A total of 2314 male subjects from the Jinuo ethnic group in China were enrolled. Of these, 986 subjects drank alcohol frequently and 404 subjects did not. Lifestyle information was gathered by using a questionnaire, and measurements of blood pressure, body mass index, blood glucose level, liver function, and kidney function were collected. GA was measured by using an enzymatic method. Frequent drinking was defined as a history of drinking ethanol > 80 g/d within the past two weeks. Nondrinking was defined as no alcohol consumption in the past three months. Subjects with an alcohol intake between 0 and 80 g/d in the past two weeks were included in the drinking-occasionally group. Analysis of variance (ANOVA), correlation analysis, and linear regression were used to evaluate the effects of drinking on serum GA levels. Decision tree regression (DTR) algorithm was used to evaluate the effect of features (variables) on GA levels. Results. We found that male subjects who drank frequently had significantly lower serum GA levels than subjects who did not drink (13.0 ± 1.7 vs. 14.1 ± 3.7, p < 0.05 ). Spearman’s correlation analysis calculated a coefficient of −0.152 between drinking and GA ( p < 0.005 ). Linear regression established that drinking was an independent predictor for GA levels with a standardized regression coefficient of −0.144 ( p < 0.05 ). Decision tree regression showed that the effect of drinking on GA levels (0.0283) is five times higher than that of smoking (0.0057). Conclusions. Frequent alcohol consumption could result in decreased GA levels in men of the Jinuo ethnic group in China.

show abstract

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

Cited by 103 publications

References 43 publications

Sirt6 opposes glycochenodeoxycholate-induced apoptosis of biliary epithelial cells through the AMPK/PGC-1α pathway

Sirt6 opposes glycochenodeoxycholate-induced apoptosis of biliary epithelial cells through the AMPK/PGC-1α pathway

Epigenetic silencing of LncRNA ANRIL enhances liver fibrosis and HSC activation through activating AMPK pathway

Serum Glycated Albumin Levels Are Affected by Alcohol in Men of the Jinuo Ethnic Group in China

Contact Info

Product

Resources

About