Histone methyltransferase G9a protects against acute liver injury through GSTP1

Abstract Acute liver injury is commonly caused by bacterial endotoxin/lipopolysaccharide (LPS), and by drug overdose such as acetaminophen (APAP). The exact role of epigenetic modification in acute liver injury remains elusive. Here, we investigated the role of histone methyltransferase G9a in LPS- or APAP overdose-induced acute liver injury. Under d-galactosamine sensitization, liver-specific G9a-deficient mice (L-G9a−/−) exhibited 100% mortality after LPS injection, while the control and L-G9a+/− littermates showed very mild mortality. Moreover, abrogation of hepatic G9a or inhibiting the methyltransferase activity of G9a aggravated LPS-induced liver damage. Similarly, under sublethal APAP overdose, L-G9a−/− mice displayed more severe liver injury. Mechanistically, ablation of G9a inhibited H3K9me1 levels at the promoters of Gstp1/2, two liver detoxifying enzymes, and consequently suppressed their transcription. Notably, treating L-G9a−/− mice with recombinant mouse GSTP1 reversed the LPS- or APAP overdose-induced liver damage. Taken together, we identify a novel beneficial role of G9a-GSTP1 axis in protecting against acute liver injury.

Download Full-text

Nicotinamide improves NAD+ levels to protect against acetaminophen-induced acute liver injury in mice

Human & Experimental Toxicology ◽

10.1177/09603271211014573 ◽

2021 ◽

pp. 096032712110145

Author(s):

J Xu ◽

L Zhang ◽

R Jiang ◽

K Hu ◽

D Hu ◽

...

Keyword(s):

Liver Injury ◽

Acute Liver Injury ◽

Related Factor ◽

Dependent Manner ◽

Nicotinamide Phosphoribosyltransferase ◽

Apap Overdose ◽

Hepatoprotective Effects ◽

Dose Dependent ◽

Different Doses

Acetaminophen (APAP) overdose causes acute liver injury (ALI). Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme, and NAD+ is oxidized type which synthesized from nicotinamide (NAM). The present study aimed to investigate the role of NAD+ in ALI and protective property of NAM. The mice were subjected to different doses APAP. After 8 hours, the serum activities of alaninetransaminase (ALT) and aspartate aminotransferase (AST), the hepatic NAD+ level and nicotinamide phosphoribosyltransferase (NAMPT) expression were determined. Then, the mice were pretreated with NAM (800 mg/kg), the hepatoprotective effects and the key antioxidative molecules were evaluated. Our findings indicated that APAP resulted in remarkable NAD+ depletion in a dose-dependent manner accompanied by NAMPT downregulation, and NAM pretreatment significantly elevated the NAD+ decline due to upregulation of NAMPT. Moreover, the downregulated Kelch-like ECH-associated protein-1 (Keap1), upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and its translocation activation after NAM administration were confirmed, which were in accordance with improved superoxide dismutase (SOD) and glutathione (GSH) levels. Finally, NAM dramatically exhibited hepatoprotective effects by reducing the liver index and necrotic area. This study has suggested that APAP impairs liver NAD+ level and NAM is able to improve hepatic NAD+ to activate antioxidant pathway against APAP-induced ALI.

Download Full-text

Susceptibility of Asialoglycoprotein Receptor-Deficient Mice to Lps/Galactosamine Liver Injury and Protection by Betaine Administration

Biology ◽

10.3390/biology10010019 ◽

2020 ◽

Vol 10 (1) ◽

pp. 19

Author(s):

Karuna Rasineni ◽

Serene M. L. Lee ◽

Benita L. McVicker ◽

Natalia A. Osna ◽

Carol A. Casey ◽

...

Keyword(s):

Liver Injury ◽

Liver Failure ◽

Liver Damage ◽

Asialoglycoprotein Receptor ◽

Fulminant Liver Failure ◽

Wild Type ◽

Tissue Samples ◽

Tnf Α ◽

Deficient Mice

Background: Work from our laboratory has shown that the ethanol-induced increase in apoptotic hepatocellular death is closely related to the impairment in the ability of the asialoglycoprotein receptor (ASGP-R) to remove neighboring apoptotic cells. In this study, we assessed the role of ASGP-R in fulminant liver failure and investigated whether prior treatment with betaine (a naturally occurring tertiary amine) is protective. Methods: Lipopolysaccharide (LPS; 50 μg/kg BW) and galactosamine (GalN; 350 mg/kg BW) were injected together to wild-type and ASGP-R-deficient mice that were treated for two weeks prior with or without 2% betaine in drinking water. The mice were sacrificed 1.5, 3, or 4.5 h post-injection, and tissue samples were collected. Results: LPS/GalN injection generate distinct molecular processes, which includes increased production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), thus causing apoptosis as evident by increased caspase-3 activity. ASGP-R deficient animals showed increased liver caspase activities, serum TNF-α and IL-6 levels, as well as more pronounced liver damage compared with the wild-type control animals after intraperitoneal injection of LPS/GalN. In addition, prior administration of betaine was found to significantly attenuate the LPS/GalN-induced increases in liver injury parameters. Conclusion: Our work underscores the importance of normal functioning of ASGP-R in preventing severe liver damage and signifies a therapeutic role of betaine in prevention of liver injuries from toxin-induced fulminant liver failure.

Download Full-text

Cannabidiol Rescues Acute Hepatic Toxicity and Seizure Induced by Cocaine

Mediators of Inflammation ◽

10.1155/2015/523418 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 22

Author(s):

Luciano Rezende Vilela ◽

Lindisley Ferreira Gomides ◽

Bruna Araújo David ◽

Maísa Mota Antunes ◽

Ariane Barros Diniz ◽

...

Keyword(s):

Liver Injury ◽

Liver Damage ◽

Acute Liver Injury ◽

Endocannabinoid System ◽

Protective Role ◽

Acute Liver Damage ◽

Protective Actions ◽

Cocaine Toxicity ◽

Hepatotoxic Drug

Cocaine is a commonly abused illicit drug that causes significant morbidity and mortality. The most severe and common complications are seizures, ischemic strokes, myocardial infarction, and acute liver injury. Here, we demonstrated that acute cocaine intoxication promoted seizure along with acute liver damage in mice, with intense inflammatory infiltrate. Considering the protective role of the endocannabinoid system against cell toxicity, we hypothesized that treatment with an anandamide hydrolysis inhibitor, URB597, or with a phytocannabinoid, cannabidiol (CBD), protects against cocaine toxicity. URB597 (1.0 mg/kg) abolished cocaine-induced seizure, yet it did not protect against acute liver injury. Using confocal liver intravital microscopy, we observed that CBD (30 mg/kg) reduced acute liver inflammation and damage induced by cocaine and prevented associated seizure. Additionally, we showed that previous liver damage induced by another hepatotoxic drug (acetaminophen) increased seizure and lethality induced by cocaine intoxication, linking hepatotoxicity to seizure dynamics. These findings suggest that activation of cannabinoid system may have protective actions on both liver and brain induced by cocaine, minimizing inflammatory injury promoted by cocaine, supporting its further clinical application in the treatment of cocaine abuse.

Download Full-text

Inhibition of histone methyltransferase G9a attenuates liver cancer initiation by sensitizing DNA-damaged hepatocytes to p53-induced apoptosis

Cell Death and Disease ◽

10.1038/s41419-020-03381-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Takuma Nakatsuka ◽

Keisuke Tateishi ◽

Hiroyuki Kato ◽

Hiroaki Fujiwara ◽

Keisuke Yamamoto ◽

...

Keyword(s):

Dna Damage ◽

Epigenetic Modification ◽

Histone Methyltransferase ◽

Preventive Strategy ◽

Tumor Initiation ◽

Liver Transcriptome ◽

Genetic Abnormalities ◽

Responsive Element ◽

Induced Apoptosis

AbstractWhile the significance of acquired genetic abnormalities in the initiation of hepatocellular carcinoma (HCC) has been established, the role of epigenetic modification remains unknown. Here we identified the pivotal role of histone methyltransferase G9a in the DNA damage-triggered initiation of HCC. Using liver-specific G9a-deficient (G9aΔHep) mice, we revealed that loss of G9a significantly attenuated liver tumor initiation caused by diethylnitrosamine (DEN). In addition, pharmacological inhibition of G9a attenuated the DEN-induced initiation of HCC. After treatment with DEN, while the induction of γH2AX and p53 were comparable in the G9aΔHep and wild-type livers, more apoptotic hepatocytes were detected in the G9aΔHep liver. Transcriptome analysis identified Bcl-G, a pro-apoptotic Bcl-2 family member, to be markedly upregulated in the G9aΔHep liver. In human cultured hepatoma cells, a G9a inhibitor, UNC0638, upregulated BCL-G expression and enhanced the apoptotic response after treatment with hydrogen peroxide or irradiation, suggesting an essential role of the G9a-Bcl-G axis in DNA damage response in hepatocytes. The proposed mechanism was that DNA damage stimuli recruited G9a to the p53-responsive element of the Bcl-G gene, resulting in the impaired enrichment of p53 to the region and the attenuation of Bcl-G expression. G9a deletion allowed the recruitment of p53 and upregulated Bcl-G expression. These results demonstrate that G9a allows DNA-damaged hepatocytes to escape p53-induced apoptosis by silencing Bcl-G, which may contribute to the tumor initiation. Therefore, G9a inhibition can be a novel preventive strategy for HCC.

Download Full-text

The Role of the Histone Methyltransferase EZH2 in Liver Inflammation and Fibrosis in STAM NASH Mice

Biology ◽

10.3390/biology9050093 ◽

2020 ◽

Vol 9 (5) ◽

pp. 93 ◽

Cited By ~ 1

Author(s):

Seul Lee ◽

Dong-Cheol Woo ◽

Jeeheon Kang ◽

Moonjin Ra ◽

Ki Hyun Kim ◽

...

Keyword(s):

Liver Disease ◽

Epigenetic Modification ◽

Treatment Options ◽

Histone Methyltransferase ◽

Alcoholic Fatty Liver ◽

Alcoholic Steatohepatitis ◽

Promising Therapeutic Target ◽

Alcoholic Fatty Liver Disease ◽

Potential Therapeutics

Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease, with few biomarkers and treatment options currently available. Non-alcoholic steatohepatitis (NASH), a progressive disease of NAFLD, may lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Epigenetic modification can contribute to the progression of NAFLD causing non-alcoholic steatohepatitis (NASH), in which the exact role of epigenetics remains poorly understood. To identify potential therapeutics for NASH, we tested small-molecule inhibitors of the epigenetic target histone methyltransferase EZH2, Tazemetostat (EPZ-6438), and UNC1999 in STAM NASH mice. The results demonstrate that treatment with EZH2 inhibitors decreased serum TNF-alpha in NASH. In this study, we investigated that inhibition of EZH2 reduced mRNA expression of inflammatory cytokines and fibrosis markers in NASH mice. In conclusion, these results suggest that EZH2 may present a promising therapeutic target in the treatment of NASH.

Download Full-text

The role of non-steroidal anti-inflammatory drugs in acute liver injury.

BMJ ◽

10.1136/bmj.305.6858.865 ◽

1992 ◽

Vol 305 (6858) ◽

pp. 865-868 ◽

Cited By ~ 70

Author(s):

L. A. Garcia Rodriguez ◽

S. Perez Gutthann ◽

A. M. Walker ◽

L. Lueck

Keyword(s):

Liver Injury ◽

Acute Liver Injury ◽

Inflammatory Drugs ◽

Anti Inflammatory

Download Full-text

Gigantol ameliorates CCl4-induced liver injury via preventing activation of JNK/cPLA2/12-LOX inflammatory pathway

Scientific Reports ◽

10.1038/s41598-020-79400-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Yaru Xue ◽

Qiangqiang Deng ◽

Qingli Zhang ◽

Zhenghua Ma ◽

Binfan Chen ◽

...

Keyword(s):

Liver Injury ◽

Acute Liver Injury ◽

Nordihydroguaiaretic Acid ◽

Hepatic Inflammation ◽

Cpla2 Activation ◽

Inflammatory Processes ◽

Mrna And Protein Expression ◽

Lox Inhibitors ◽

Jnk Activation

AbstractArachidonic acid (AA) signaling pathway is an important constituent of inflammatory processes. In our previous study, it was found that dihydro-stilbene gigantol relieved hepatic inflammation in mice with CCl4-induced acute liver injury. This study aimed to investigate the involvement of arachidonate metabolic cascade in this process. Our results showed CCl4 activated AA metabolism with the evidence of cPLA2 phosphorylation, which was dependent on the MAPK/JNK activation. Pretreatment with JNK inhibitor SU3327 or gigantol abolished the cPLA2 activation, along with the attenuation of liver damage. Besides, gigantol markedly decreased immune cells activation. Metabolomic analysis revealed that gigantol universally reversed the upregulation of major AA metabolites in injured mouse livers induced by CCl4, especially 12-hydroxyeicosatetraenoic acid (12-HETE). Gigantol also decreased the mRNA and protein expression of platelet-, and leukocyte-type 12-lipoxxygenase (LOX) in the liver. Furthermore, pan-LOX inhibitor nordihydroguaiaretic acid (NDGA) and specific 12-LOX inhibitors baicalein and ML351 attenuated the liver injury to the same extent as gigantol. Overall, our study elucidated a comprehensive profile of AA metabolites during hepatic inflammation caused by CCl4, highlighting the role of 12-LOX-12-HETE pathway in this process. And gigantol alleviated liver inflammation partly through inhibiting the JNK/cPLA2/12-LOX pathway.

Download Full-text