scholarly journals Protective functions of ZO-2/Tjp2 expressed in hepatocytes and cholangiocytes against liver injury and cholestasis

2019 ◽  
Author(s):  
Jianliang Xu ◽  
P. Jaya P. Kausalya ◽  
Noémi Van Hul ◽  
Matias J. Caldez ◽  
Shiyi Xu ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Injury ◽  
Mouse Liver ◽  
Liver Function Tests ◽  
Protective Role ◽  
Detoxification Enzymes ◽  
Cholestatic Liver Disease ◽  
Missense Mutations ◽  
Expression Levels ◽  
Underlying Mechanisms

BACKGROUND & AIMSTight junctions (TJs) establish tissue barriers that maintain osmotic homeostasis and, in the liver, isolate bile flow from the blood circulation. ZO-2/Tjp2 is a scaffold protein that tethers TJ transmembrane proteins to the actin cytoskeleton. Missense mutations in Tjp2 have recently been shown to cause progressive cholestatic liver disease in humans. However, the underlying mechanisms still remain elusive. To study the role of Tjp2 in cholestatic liver disease, we generated and characterized mice lacking Tjp2 in hepatocytes, cholangiocytes, or both.METHODSTjp2 was inactivated in the mouse liver (both in hepatocytes and cholangiocytes) or hepatocytes or cholangiocytes only. Liver function tests were carried out by biochemical analysis of plasma and liver samples and liver tissue was evaluated by immunohistochemistry and histology. The mice were also subjected to cholic acid (CA) diet to assess their susceptibility to liver insults.RESULTSDeletion of Tjp2 in the mouse liver did not result in apparent changes in TJ structure and composition, but lead to progressive cholestasis with lower expression levels of the bile acid (BA) transporter ABCB11/Bsep and the detoxification enzyme Cyp2b10. Feeding a CA diet that is well tolerated by control mice caused severe cholestasis and necrotic liver injury in mice lacking hepatic Tjp2. Administration of a CAR agonist, TCPOBOP, protected these mice from CA induced injury by enhancing the expression of the detoxifying enzyme Cyp2b10 in hepatocytes. Mice lacking Tjp2 in only hepatocytes or in only cholangiocytes showed less severe CA diet induced liver injury.CONCLUSIONLoss of Tjp2 from hepatocytes and cholangiocytes both contribute to progressive cholestatic liver disease and higher susceptibility to liver injury. In hepatocytes, Tjp2 exerts a protective role by regulating expression levels of BA transporters and detoxification enzymes. The mice may provide a new animal model for cholestatic liver disease linked to Tjp2 mutations in humans.

scholarly journals Protective Role of Estrogen-induced miRNA-29 Expression in Carbon Tetrachloride-induced Mouse Liver Injury

2012 ◽  
Vol 287 (18) ◽  
pp. 14851-14862 ◽  
Author(s):  
Yaqin Zhang ◽  
Linping Wu ◽  
Yang Wang ◽  
Mingcao Zhang ◽  
Limin Li ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Injury ◽  
Mouse Liver ◽  
Protective Role

Liver Injury in Patients With Cholestatic Liver Disease Treated With Obeticholic Acid

Hepatology ◽  
2020 ◽  
Vol 71 (4) ◽  
pp. 1511-1514 ◽  
Author(s):  
John E. Eaton ◽  
Raj Vuppalanchi ◽  
Rajender Reddy ◽  
Sanjaya K. Satapathy ◽  
Bilal Ali ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Injury ◽  
Cholestatic Liver Disease ◽  
Obeticholic Acid

scholarly journals Mechanisms of liver disease: cross-talk between the NF-κB and JNK pathways

2009 ◽  
Vol 390 (10) ◽  
Author(s):  
Salvatore Papa ◽  
Concetta Bubici ◽  
Francesca Zazzeroni ◽  
Guido Franzoso
Keyword(s):  
Cell Death ◽  
Liver Disease ◽  
Liver Injury ◽  
Cellular Response ◽  
Protective Role ◽  
Activation Of Transcription ◽  
Tnf Α ◽  
Infected Cells ◽  
Hepatocyte Death ◽  
Necrosis Factor

Abstract The liver plays a central role in the transformation and degradation of endogenous and exogenous chemicals, and in the removal of unwanted cells such as damaged, genetically mutated and virus-infected cells. Because of this function, the liver is susceptible to toxicity caused by the products generated during these natural occurrences. Hepatocyte death is the major feature of liver injury. In response to liver injury, specific intracellular processes are initiated to maintain liver integrity. Inflammatory cytokines including tumor necrosis factor (TNF)α and interleukin-6 (IL-6) are key mediators of these processes and activate different cellular response such as proliferation, survival and death. TNFα induces specific signaling pathways in hepatocytes that lead to activation of either pro-survival mediators or effectors of cell death. Whereas activation of transcription factor NF-κB promotes survival, c-Jun N-terminal kinases (JNKs) and caspases are strategic effectors of cell death in the TNFα-mediated signaling pathway. This review summarizes recent advances in the mechanisms of TNFα-induced hepatotoxicity and suggests that NF-κB plays a protective role against JNK-induced hepatocyte death. Identification of the mechanisms regulating interplay between the NF-κB and JNK pathways is required in the search for novel targets for the treatment of liver disease, including hepatitis and hepatocellular carcinoma.

scholarly journals Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0244743
Author(s):  
Sarah A. Taylor ◽  
Shang-Yang Chen ◽  
Gaurav Gadhvi ◽  
Liang Feng ◽  
Kyle D. Gromer ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Injury ◽  
Single Cell ◽  
Transcriptional Profile ◽  
Cholestatic Liver Disease ◽  
Hepatic Macrophages ◽  
Single Cell Rna Sequencing ◽  
Macrophage Populations ◽  
Cholestatic Liver Injury ◽  
Macrophage Subsets

Background & aims Limited understanding of the role for specific macrophage subsets in the pathogenesis of cholestatic liver injury is a barrier to advancing medical therapy. Macrophages have previously been implicated in both the mal-adaptive and protective responses in obstructive cholestasis. Recently two macrophage subsets were identified in non-diseased human liver; however, no studies to date fully define the heterogeneous macrophage subsets during the pathogenesis of cholestasis. Here, we aim to further characterize the transcriptional profile of macrophages in pediatric cholestatic liver disease. Methods We isolated live hepatic immune cells from patients with biliary atresia (BA), Alagille syndrome (ALGS), and non-cholestatic pediatric liver by fluorescence activated cell sorting. Through single-cell RNA sequencing analysis and immunofluorescence, we characterized cholestatic macrophages. We next compared the transcriptional profile of pediatric cholestatic and non-cholestatic macrophage populations to previously published data on normal adult hepatic macrophages. Results We identified 3 distinct macrophage populations across cholestatic liver samples and annotated them as lipid-associated macrophages, monocyte-like macrophages, and adaptive macrophages based on their transcriptional profile. Immunofluorescence of liver tissue using markers for each subset confirmed their presence across BA (n = 6) and ALGS (n = 6) patients. Cholestatic macrophages demonstrated reduced expression of immune regulatory genes as compared to normal hepatic macrophages and were distinct from macrophage populations defined in either healthy adult or pediatric non-cholestatic liver. Conclusions We are the first to perform single-cell RNA sequencing on human pediatric cholestatic liver and identified three macrophage subsets with distinct transcriptional signatures from healthy liver macrophages. Further analyses will identify similarities and differences in these macrophage sub-populations across etiologies of cholestatic liver disease. Taken together, these findings may allow for future development of targeted therapeutic strategies to reprogram macrophages to an immune regulatory phenotype and reduce cholestatic liver injury.

scholarly journals Characteristics and outcomes of patients with COVID-19 and liver injury: a retrospective analysis and a multicenter experience

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Andrei Voiosu ◽  
Adina Roman ◽  
Ruxandra Pop ◽  
Alina Boeriu ◽  
Cristiana Popp ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Injury ◽  
Liver Function ◽  
Chronic Liver Disease ◽  
Liver Function Tests ◽  
Chronic Liver ◽  
Upper Limit ◽  
Function Tests ◽  
Elevated Liver Function Tests ◽  
Negative Outcome

Abstract Background and aims: Patients with COVID-19 frequently present abnormal elevated liver function tests of unknown clinical significance. We aimed to investigate the characteristics and factors influencing outcome in patients with confirmed SARS-CoV-2 infection and liver injury on admission. Methods: This is a retrospective observational study of patients hospitalized in two COVID units in Romania. Relevant data on clinical and laboratory parameters and medication administered during the admission were analyzed to identify predictors of a negative outcome. Patients with confirmed COVID-19 and liver function tests (LFTs) above the upper limit of normal were included in the analysis. Results: From 1,207 patients, we identified 134 patients (11%) with abnormal LFTs during hospitalization. The majority of patients had mildly elevated levels and a predominantly cholestatic pattern of liver injury. Patients who received lopinavir/ritonavir were more likely to have increased ALAT levels (p<0.0001). Sixteen patients had pre-existing chronic liver disease, and they were more likely to suffer from severe COVID-19 (p=0.009) and have a negative outcome (p<0.001), but on multivariate analysis, only the severity of COVID-19 was predictive of death (OR 69.9; 95% CI 6.4-761.4). Conclusions: Mild liver injury is relatively common in COVID-19 and possibly influenced by medication. Patients with chronic liver disease are at high risk for negative outcome, but the severity of the infection is the only predictor of death.

scholarly journals Pterostilbene Alleviates Cholestasis by Promoting SIRT1 Activity in Hepatocytes and Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Chuanrui Ma ◽  
Jiaqing Xiang ◽  
Guixiao Huang ◽  
Yaxi Zhao ◽  
Xinyu Wang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Signaling Pathway ◽  
Cholestatic Liver Disease ◽  
P53 Signaling ◽  
Promising Target ◽  
Underlying Mechanisms ◽  
Cholestatic Liver Injury ◽  
P53 Signaling Pathway

Background and purpose: FXR is a promising target for the treatment of human cholestatic liver disease (CLD). SIRT1 is a deacetylase which promotes FXR activity through deacetylating FXR. Pterostilbene (PTE) is an activator of SIRT1. However, the role of PTE in cholestasis has so far not been investigated. We examined whether PTE treatment alleviate liver injury in DDC or ANIT-induced experimental cholestasis, and explored the underlying mechanisms.Experimental approach: Mice with DDC- or ANIT-induced cholestasis were treated with different dose of PTE. Primary hepatocytes and bone marrow derived macrophages were used in vitro to assess the molecular mechanism by which PTE may improve CLD. Identical doses of UDCA or PTE were administered to DDC- or ANIT-induced cholestasis mice.Key results: PTE intervention attenuated DDC or ANIT-induced cholestasis. PTE inhibited macrophage infiltration and activation in mouse liver through the SIRT1-p53 signaling pathway, and it improved hepatic bile metabolism through the SIRT1-FXR signaling pathway. Compare with UDCA, the same doses of PTE was more effective in improving cholestatic liver injury caused by DDC or ANIT.Conclusion and implications: SIRT1 activation in macrophages may be an effective CLD treatment avenue. Using CLD models, we thus identified PTE as a novel clinical candidate compound for the treatment of CLD.

scholarly journals Liver Injury in Patients with COVID-19 without Underlying Liver Disease

2022 ◽  
Vol 11 (2) ◽  
pp. 308
Author(s):  
Monika Pazgan-Simon ◽  
Sylwia Serafińska ◽  
Michał Kukla ◽  
Marta Kucharska ◽  
Jolanta Zuwała-Jagiełło ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Injury ◽  
Vascular Endothelial Cells ◽  
Signs And Symptoms ◽  
Liver Function Tests ◽  
Underlying Mechanism ◽  
Underlying Liver Disease ◽  
Pattern Of Injury ◽  
Laboratory Test Results ◽  
Type Pattern

SARS-CoV-2 shows a high affinity for the ACE-2 receptor, present on the epithelial cells of the upper and lower respiratory tract, within the intestine, kidneys, heart, testes, biliary epithelium, and—where it is particularly challenging—on vascular endothelial cells. Liver involvement is a rare manifestation of COVID-19. Material and Methods: We reviewed 450 patients admitted due to the fact of SARS-CoV-2 infection (COVID-19) including 88 with liver injury. Based on medical history and previous laboratory test results, we excluded cases of underlying liver disease. The analysis involved a clinical course of COVID-19 in patients without underlying liver disease as well as the type and course of liver injury. Results: Signs and symptoms of liver injury were present in 20% of patients, mostly presenting as a mixed-type pattern of injury with less common cases of standalone hepatocellular (parenchymal) or cholestatic injury. The liver injury symptoms resolved at the end of inpatient treatment in 20% of cases. Sixteen patients died with no cases where liver injury would be deemed a cause of death. Conclusions: (1) Liver injury secondary to COVID-19 was mild, and in in 20%, the signs and symptoms of liver injury resolved by the end of hospitalization. (2) It seems that liver injury in patients with COVID-19 was not associated with a higher risk of mortality. (3) The underlying mechanism of liver injury as well as its sequelae are not fully known. Therefore, caution and further monitoring are advised, especially in patients whose liver function tests have not returned to normal values.

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 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&lt;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&lt;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&lt;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

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