scholarly journals A187 CHOLESTATIC LIVER DISEASE AND BRAIN DYSFUNCTION: ROLE OF THE ARYL HYDROCARBON RECEPTOR

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 58-59
Author(s):  
A J Mathews ◽  
F Vicentini ◽  
L Swain ◽  
M Swain ◽  
K A Sharkey
Keyword(s):  
Liver Disease ◽  
Social Interaction ◽  
Liver Injury ◽  
Aryl Hydrocarbon Receptor ◽  
Brain Dysfunction ◽  
Cholestatic Liver Disease ◽  
Aryl Hydrocarbon ◽  
Duct Ligation ◽  
The Brain

Abstract Background Cholestatic liver disease is associated with immune-mediated inflammatory liver injury. This disorder is also associated with brain dysfunction and behavioural changes, notably fatigue, depression and social withdrawal. The mechanisms leading to these central nervous system abnormalities are unknown, however, they are associated with neuroinflammation. Microglia and astrocytes are two glial populations that play key roles in neuroinflammation. Activated glia display morphological changes, secrete cytokines, and mediate electrophysiological changes, altering the normal functioning of the brain. The aryl hydrocarbon receptor (AhR) is a transcription factor involved in the immune response. AhR is present on glia and its’ activation has been shown to reduce neuroinflammation. The role of the AhR in cholestatic liver disease has yet to be examined. Aims To study the function of the AhR in a model of cholestic liver disease. We will test the hypothesis that activation of AhR in the brain will reduce neuroinflammation and behavioral deficits observed in cholestatic mice. Methods Male C57Bl/6J mice had cholestasis induced by bile duct ligation (BDL); comparisons were made to sham-operated controls. Mice were tested for social interaction with a 4-week old juvenile in their home cage and the number of social interaction attempts quantified. Next, mice were euthanized, brains were removed and processed for immunohistochemistry. Brain sections were stained for markers of microglia (IBA-1) and astrocytes (GFAP). Microglia were counted and astrocyte activation was qualitatively assessed. PCR was used to quantify gene expression of AhR and its downstream gene targets (eg. CYP1A1) in mice that recived treatment with beta-napthoflavone (BNF), an AhR agonist, or in vehicle treated controls. Results BDL mice made significantly fewer attempts to interact with the juvenile as compared to controls (P<0.05). We also observed a significant increase in IBA-1 immunoreactive cell numbers in both the CA1 region of the hippocampus and the hypothalamic paraventricular nucleus (PVN, P<0.05). BDL mice also displayed marked increases in GFAP+ staining in the PVN, but not the CA1, in contrast to sham controls. Lastly, we found that BNF significantly upregulated CYP1A1 (P<0.05) in the liver and prefrontal cortex of mice. We are currently examining whether BNF can reduce neuroinflammation and improve decreased social interaction in cholestatic mice. Conclusions Cholestatic liver damage was associated with impaired social behavior. Further, glial activation, an indicator of neuroinflammation was increased in components of the limbic system associated with the response to stress, learning, and memory. Future experiments will address whether activation of the AhR will ameliorate neuroinflammation and behavioral changes observed in mice with cholestatic liver injury. Funding Agencies CCC, CIHR

CHOLESTATIC LIVER DISEASE AND BRAIN DYSFUNCTION: ROLE OF THE ARYL HYDROCARBON RECEPTOR

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Alexander Joseph Mathews ◽  
Fernando Augusto Vicentini ◽  
Liam Andrew Swain ◽  
Mark Gordon Swain ◽  
Keith Alexander Sharkey
Keyword(s):  
Liver Disease ◽  
Aryl Hydrocarbon Receptor ◽  
Brain Dysfunction ◽  
Cholestatic Liver Disease ◽  
Aryl Hydrocarbon

scholarly journals Microbiota tryptophan metabolism induces aryl hydrocarbon receptor activation and improves alcohol-induced liver injury

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321565 ◽  
Author(s):  
Laura Wrzosek ◽  
Dragos Ciocan ◽  
Cindy Hugot ◽  
Madeleine Spatz ◽  
Margot Dupeux ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Injury ◽  
Aryl Hydrocarbon Receptor ◽  
Intestinal Microbiota ◽  
Alcoholic Liver Disease ◽  
Receptor Activation ◽  
Liver Lesions ◽  
Knock Out ◽  
Aryl Hydrocarbon ◽  
Tryptophan Metabolites

ObjectiveChronic alcohol consumption is an important cause of liver-related deaths. Specific intestinal microbiota profiles are associated with susceptibility or resistance to alcoholic liver disease in both mice and humans. We aimed to identify the mechanisms by which targeting intestinal microbiota can improve alcohol-induced liver lesions.DesignWe used human associated mice, a mouse model of alcoholic liver disease transplanted with the intestinal microbiota of alcoholic patients and used the prebiotic, pectin, to modulate the intestinal microbiota. Based on metabolomic analyses, we focused on microbiota tryptophan metabolites, which are ligands of the aryl hydrocarbon receptor (AhR). Involvement of the AhR pathway was assessed using both a pharmacological approach and AhR-deficient mice.ResultsPectin treatment modified the microbiome and metabolome in human microbiota-associated alcohol-fed mice, leading to a specific faecal signature. High production of bacterial tryptophan metabolites was associated with an improvement of liver injury. The AhR agonist Ficz (6-formylindolo (3,2-b) carbazole) reduced liver lesions, similarly to prebiotic treatment. Conversely, inactivation of the ahr gene in alcohol-fed AhR knock-out mice abrogated the beneficial effects of the prebiotic. Importantly, patients with severe alcoholic hepatitis have low levels of bacterial tryptophan derivatives that are AhR agonists.ConclusionsImprovement of alcoholic liver disease by targeting the intestinal microbiota involves the AhR pathway, which should be considered as a new therapeutic target.

The Role of Aryl Hydrocarbon Receptor in PCB-Induced Fatty Liver Disease in Mice

2017 ◽  
Vol 152 (5) ◽  
pp. S1108-S1109
Author(s):  
Hongxue Shi ◽  
Heather Clair ◽  
Josiah Hardesty ◽  
Jian Jin ◽  
Cameron Falkner ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Aryl Hydrocarbon Receptor ◽  
Fatty Liver Disease ◽  
Aryl Hydrocarbon

Activation of the Glutathione Peroxidase by Metformin in the Bile-duct Ligation induced Liver Injury: In vivo Combined with Molecular Docking Studies

2018 ◽  
Vol 24 (27) ◽  
pp. 3256-3263 ◽  
Author(s):  
Mahboubeh Mansourian ◽  
Hossein Sadeghi ◽  
Amir Hossein Doustimotlagh
Keyword(s):  
Antioxidant Enzymes ◽  
Molecular Docking ◽  
Liver Disease ◽  
Bile Duct ◽  
Liver Injury ◽  
Glutathione Peroxidase ◽  
Bile Duct Ligation ◽  
Cholestatic Liver Disease ◽  
Hydroxyproline Content ◽  
Duct Ligation

Background: Inhibition of hepatic fibrosis is an attainable objective in managing the chronic liver disease. The present study aimed to investigate possible defensive effects of metformin on the activities of antioxidant enzymes, hydroxyproline content, and biochemical factors in bile duct ligation (BDL)-induced cholestatic rats. The interactive behavior of metformin with glutathione peroxidase (GPx) enzyme was also explained by molecular docking and conformation characterization. Methods: The present study was conducted on 28-adult male Wistar rats classified into four 7-animal groups: sham-control, mere BDL, and BDL+ metformin that received daily metformin as gavage in two doses of 250 and 500 mg/kg bw for 10 days. Biochemical analysis, hydroxyproline content, and antioxidant enzymes activity were also determined. Results: The hydroxyproline content significantly increased, but the GPx enzyme activity significantly decreased in the hepatic tissue following BDL, indicating that an oxidative stress-related model in rats was successfully constituted. Administration of metformin at two doses attenuated hydroxyproline content in the cholestatic liver and ameliorated the depletion of GPx enzyme activities compared to the non-treated BDL group (P-value ≤ 0.05). Molecular docking study provides the evidence for metformin ability to regulate enzymatic activity of GPx. Conclusion: The research data indicated that due to novel hepatoprotective effects of metformin in an animal model with BDL-induced liver injury, it was a potential beneficial therapeutic agent for treating the cholestatic liver disease. The main mechanism might contribute to antioxidant actions, particularly via GPx enzyme.

scholarly journals ADAM Metalloproteinase Domain 17 Regulates Cholestasis-Associated Liver Injury and Sickness Behavior Development in Mice

2022 ◽  
Vol 12 ◽  
Author(s):  
Wagdi Almishri ◽  
Liam A. Swain ◽  
Charlotte D’Mello ◽  
Tyson S. Le ◽  
Stefan J. Urbanski ◽  
...  
Keyword(s):  
Liver Injury ◽  
Protein Expression ◽  
Adhesion Molecules ◽  
Specific Inhibitor ◽  
Sickness Behavior ◽  
Cholestatic Liver Disease ◽  
Behavior Development ◽  
Duct Ligation ◽  
Cholestatic Liver Injury

Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) is a ubiquitously expressed membrane-bound enzyme that mediates shedding of a wide variety of important regulators in inflammation including cytokines and adhesion molecules. Hepatic expression of numerous cytokines and adhesion molecules are increased in cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), however, the pathophysiological role of ADAM17 in regulating these conditions remains unknown. Therefore, we evaluated the role of ADAM17 in a mouse model of cholestatic liver injury due to bile duct ligation (BDL). We found that BDL enhanced hepatic ADAM17 protein expression, paralleled by increased ADAM17 bioactivity. Moreover, inhibition of ADAM17 bioactivity with the specific inhibitor DPC 333 significantly improved both biochemical and histological evidence of liver damage in BDL mice. Patients with cholestatic liver disease commonly experience adverse behavioral symptoms, termed sickness behaviors. Similarly, BDL in mice induces reproducible sickness behavior development, driven by the upregulated expression of cytokines and adhesion molecules that are in turn regulated by ADAM17 activity. Indeed, inhibition of ADAM17 activity significantly ameliorated BDL-associated sickness behavior development. In translational studies, we evaluated changes in ADAM17 protein expression in liver biopsies obtained from patients with PBC and PSC, compared to normal control livers. PSC and PBC patients demonstrated increased hepatic ADAM17 expression in hepatocytes, cholangiocytes and in association with liver-infiltrating immune cells compared to normal controls. In summary, cholestatic liver injury in mice and humans is associated with increased hepatic ADAM17 expression. Furthermore, inhibition of ADAM17 activity improves both cholestatic liver injury and associated sickness behavior development, suggesting that ADAM17 inhibition may represent a novel therapeutic approach for treating patients with PBC/PSC.

scholarly journals The aryl hydrocarbon receptor in liver inflammation

2021 ◽  
Author(s):  
Antonella Carambia ◽  
Fenja Amrei Schuran
Keyword(s):  
Liver Disease ◽  
Immune Responses ◽  
Aryl Hydrocarbon Receptor ◽  
Current Knowledge ◽  
Regulatory Factor ◽  
Potential Therapeutic Target ◽  
Adaptive Immune ◽  
Aryl Hydrocarbon ◽  
Healthy Liver

AbstractThe aryl hydrocarbon receptor (AHR) is a ubiquitously expressed ligand-activated transcription factor with multifaceted physiological functions. In the immune system, AHR has been unequivocally identified as a key regulatory factor that can integrate environmental, dietary, or microbial signals into innate and adaptive immune responses. Correspondingly, AHR activity seems to be most important at barrier organs, such as the gut, skin, and lung. The liver is likewise prominently exposed to gut-derived dietary or microbial AHR ligands and, moreover, generates plenty of AHR ligands itself. Yet, surprisingly little is known about the role of AHR in the regulation of hepatic immune responses, which are normally biased towards tolerance, preventing harmful inflammation in response to innocuous stimuli. In this review, we summarize the current knowledge about the role of AHR in hepatic immune responses in the healthy liver as well as in inflammatory liver disease. Moreover, we discuss AHR as a potential therapeutic target in hepatic disorders, including autoimmune liver disease, liver fibrosis, and liver cancer.

scholarly journals Characterizing the Role of HMG-CoA Reductase in Aryl Hydrocarbon Receptor-Mediated Liver Injury in C57BL/6 Mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Peter Dornbos ◽  
Amanda Jurgelewicz ◽  
Kelly A. Fader ◽  
Kurt Williams ◽  
Timothy R. Zacharewski ◽  
...  
Keyword(s):  
Liver Injury ◽  
Aryl Hydrocarbon Receptor ◽  
Cholesterol Biosynthesis ◽  
Competitive Inhibitor ◽  
Cholesterol Homeostasis ◽  
Hepatic Glycogen ◽  
Alcoholic Fatty Liver ◽  
Female Mice ◽  
Aryl Hydrocarbon ◽  
The Impact

Abstract The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. The prototypical ligand of the AHR is an environmental contaminant called 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD exposure is associated with many adverse health outcomes in humans including non-alcoholic fatty liver disease (NAFLD). Previous studies suggest that AHR ligands alter cholesterol homeostasis in mice through repression of genes involved in cholesterol biosynthesis, such as Hmgcr, which encodes the rate-limiting enzyme of cholesterol biosynthesis called 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR). In this study, we sought to characterize the impact of HMGCR repression in TCDD-induced liver injury. C57BL/6 mice were exposed to TCDD in the presence or absence of simvastatin, a competitive inhibitor of HMGCR. Simvastatin exposure decreased TCDD-induced hepatic lipid accumulation in both sexes, but was most prominent in females. Simvastatin and TCDD (S + T) co-treatment increased hepatic AHR-battery gene expression and liver injury in male, but not female, mice. In addition, the S + T co-treatment led to an increase in hepatic glycogen content that coincides with heavier liver in female mice. Results from this study suggest that statins, which are amongst the most prescribed pharmaceuticals, may protect from AHR-mediated steatosis, but alter glycogen metabolism and increase the risk of TCDD-elicited liver damage in a sex-specific manner.

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