scholarly journals The Role of Vitamin K in Cholestatic Liver Disease

Nutrients ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 2515
Author(s):  
Halima Sultana ◽  
Michio Komai ◽  
Hitoshi Shirakawa
Keyword(s):  
Liver Disease ◽  
Vitamin K ◽  
Animal Studies ◽  
Critical Role ◽  
Pregnane X Receptor ◽  
Primary Biliary Cholangitis ◽  
Cholestatic Liver Disease ◽  
Risk Of Death ◽  
Duct Ligation ◽  
Related Liver Disease

Vitamin K (VK) is a ligand of the pregnane X receptor (PXR), which plays a critical role in the detoxification of xenobiotics and metabolism of bile acids. VK1 may reduce the risk of death in patients with chronic liver failure. VK deficiency is associated with intrahepatic cholestasis, and is already being used as a drug for cholestasis-induced liver fibrosis in China. In Japan, to treat osteoporosis in patients with primary biliary cholangitis, VK2 formulations are prescribed, along with vitamin D3. Animal studies have revealed that after bile duct ligation-induced cholestasis, PXR knockout mice manifested more hepatic damage than wild-type mice. Ligand-mediated activation of PXR improves biochemical parameters. Rifampicin is a well-known human PXR ligand that has been used to treat intractable pruritus in severe cholestasis. In addition to its anti-cholestatic properties, PXR has anti-fibrotic and anti-inflammatory effects. However, because of the scarcity of animal studies, the mechanism of the effect of VK on cholestasis-related liver disease has not yet been revealed. Moreover, the application of VK in cholestasis-related diseases is controversial. Considering this background, the present review focuses on the effect of VK in cholestasis-related diseases, emphasizing its function as a modulator of PXR.

scholarly journals Cholangiocyte-Derived Exosomal lncRNA H19 Promotes Macrophage Activation and Hepatic Inflammation under Cholestatic Conditions

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 190 ◽  
Author(s):  
Xiaojiaoyang Li ◽  
Runping Liu ◽  
Yanyan Wang ◽  
Weiwei Zhu ◽  
Derrick Zhao ◽  
...  
Keyword(s):  
Kupffer Cells ◽  
Noncoding Rna ◽  
Macrophage Activation ◽  
Critical Role ◽  
Vital Role ◽  
Primary Biliary Cholangitis ◽  
M1 Polarization ◽  
Hepatic Macrophages ◽  
Duct Ligation ◽  
Almost All

Activation of hepatic macrophages represents the critical driving force to promote cholestatic liver injury. Exosomes, as important small extracellular vesicles released by almost all types of cells, contribute to intercellular communication. We previously reported that cholangiocyte-derived exosomal long noncoding RNA (lncRNA) H19 plays a vital role in disrupting bile acid homeostasis in hepatocytes and promoting the activation of hepatic stellate cells (HSCs). Exosomal H19 derived from cholangiocytes was rapidly taken up by Kupffer cells. However, the mechanistic links between exosomal lncRNA H19 and macrophage-driven inflammation in cholestasis remain unclear. Here, we reported that the hepatic H19 level was closely correlated with macrophage activation and hepatic fibrosis in both Mdr2-/- and bile duct ligation (BDL) cholestatic mouse models, as well as in human primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) patients. Exosomal H19 significantly induced the expression and secretion of chemokine (C–C motif) ligand 2 (CCL-2) and interleukin 6 (IL-6) in Kupffer cells. H19-enriched exosomes enhanced the activation M1 polarization of Kupffer cells and promoted the recruitment and differentiation of bone marrow-derived macrophages, which were inhibited by a CCL-2 pharmacological inhibitor. In conclusion, Cholangiocyte-derived exosomal H19 played a critical role in macrophage activation, differentiation, and chemotaxis through CCL-2/CCR-2 signaling pathways, which represent a therapeutic target for cholestatic liver diseases.

scholarly journals Practical strategies for pruritus management in the obeticholic acid-treated patient with PBC: proceedings from the 2018 expert panel

2019 ◽  
Vol 6 (1) ◽  
pp. e000256 ◽  
Author(s):  
Jennifer Pate ◽  
Juilo A Gutierrez ◽  
Catherine T Frenette ◽  
Aparna Goel ◽  
Sonal Kumar ◽  
...  
Keyword(s):  
Liver Disease ◽  
Patient Adherence ◽  
Treated Patient ◽  
Management Strategies ◽  
Primary Biliary Cholangitis ◽  
Cholestatic Liver Disease ◽  
Common Symptom ◽  
Obeticholic Acid ◽  
Intrahepatic Bile Ducts ◽  
Patient Health

Background and aimsThis article provides expert guidance on the management of pruritus symptoms in patients receiving obeticholic acid (OCA) as treatment for primary biliary cholangitis (PBC). PBC is a chronic, autoimmune cholestatic liver disease that affects intrahepatic bile ducts. If not adequately treated, PBC can lead to cholestasis and end-stage liver disease, which may require transplant. Timely treatment is therefore vital to patient health. Pruritus is a common symptom in patients with PBC. Additionally, the use of OCA to treat PBC can contribute to increased pruritus severity in some patients, adding to patient discomfort, decreasing patient quality of life (QoL), and potentially affecting patient adherence to OCA treatment.MethodsIn May 2018, a group of physician experts from the fields of gastroenterology, hepatology, and psychiatry met to discuss the management of pruritus in OCA-treated patients with PBC. Recognizing the importance of optimizing treatment for PBC, these experts developed recommendations for managing pruritus symptoms in the OCA-treated PBC patient based on their experience in clinical practice.ResultsThese recommendations include a comprehensive list of management strategies (including over-the-counter, prescription, and alternative therapies), guidance on titration of OCA to minimize pruritus severity, and an algorithm that outlines a practical approach to follow up with patients receiving OCA, to better assess and manage pruritus symptoms.ConclusionsPruritus associated with OCA therapy is dose dependent and often manageable, and with the proper education and tools, most pruritus cases can be effectively managed to minimize treatment discontinuation.

scholarly journals TGF-β2 silencing to target biliary-derived liver diseases

Gut ◽  
2020 ◽  
Vol 69 (9) ◽  
pp. 1677-1690 ◽  
Author(s):  
Anne Dropmann ◽  
Steven Dooley ◽  
Bedair Dewidar ◽  
Seddik Hammad ◽  
Tatjana Dediulia ◽  
...  
Keyword(s):  
Liver Disease ◽  
Transforming Growth Factor Beta ◽  
Liver Tissue ◽  
Liver Diseases ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Inflammatory Cells ◽  
Mechanistic Explanation ◽  
Primary Biliary Cholangitis ◽  
Cholestatic Liver Disease

ObjectiveTGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases.DesignAs we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels.ResultsTgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue.ConclusionsTaken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development.

scholarly journals Novel Insights of Primary Sclerosing Cholangitis and Primary Biliary Cholangitis

2020 ◽  
Vol 25 (2) ◽  
pp. 107-117
Author(s):  
Dong-Won Ahn
Keyword(s):  
Liver Transplantation ◽  
Liver Disease ◽  
Primary Sclerosing Cholangitis ◽  
Liver Diseases ◽  
Sclerosing Cholangitis ◽  
Acute Cholangitis ◽  
Magnetic Resonance Cholangiopancreatography ◽  
Primary Biliary Cholangitis ◽  
Cholestatic Liver Disease ◽  
Biliary Cirrhosis

Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are immune-mediated chronic liver diseases. PSC is a rare disorder characterized by multi-focal bile duct strictures and progressive liver diseases, in which liver transplantation is required ultimately in most patients. Imaging studies such as magnetic resonance cholangiopancreatography have important role in diagnosis in most cases of PSC. PSC is usually accompanied by inflammatory bowel disease and there is a high risk of cholangiocarcinoma and colorectal cancer in PSC. No medical therapies have been proven to delay progression of PSC. Endoscopic intervention for tissue diagnosis or biliary drainage is frequently required in cases of PSC with dominant stricture, acute cholangitis, or clinically suspected cholangiocarcinoma. PBC is a chronic inflammatory autoimmune cholestatic liver disease, which when untreated will culminate in endstage biliary cirrhosis requiring liver transplantation. Diagnosis is usually based on the presence of serum liver tests indicative of a cholestatic hepatitis in association with circulating antimitochondrial antibodies. Patient presentation and course can be diverse in PBC and risk stratification is important to ensure all patients receive a personalised approach to their care. Medical therapy using ursodeoxycholic acid (UDCA) or obeticholic acid (OCA) has an important role to reduce the progression to end-stage liver disease in PBC.

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<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

Body distribution of stable copper isotopes during the progression of cholestatic liver disease induced by common bile duct ligation in mice

Metallomics ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 1093-1103 ◽  
Author(s):  
Marta Costas-Rodríguez ◽  
Sanne Van Campenhout ◽  
Agustina A. M. B. Hastuti ◽  
Lindsey Devisscher ◽  
Hans Van Vlierberghe ◽  
...  
Keyword(s):  
Liver Disease ◽  
Bile Duct ◽  
Common Bile Duct ◽  
Bile Duct Ligation ◽  
The Body ◽  
Cholestatic Liver Disease ◽  
Common Bile Duct Ligation ◽  
Body Distribution ◽  
Duct Ligation ◽  
Severity Of The Disease

The effect of cholestatic liver disease on the body Cu isotopic distribution was investigated in a common bile duct ligation mouse model. The isotopic composition of Cu in serum and organs becomes gradually lighter with increasing severity of the disease.

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