Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4-/- MiceSummary
Background & Aims: The endocannabinoid system is involved in the modulation of inflammatory, fibrotic, metabolic, and carcinogenesis-associated signaling pathways via cannabinoid receptor (CB)1 and CB2. We hypothesized that the pharmacologic antagonization of CB1 receptor improves cholestasi...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X21002630 |
| _version_ | 1819326780644786176 |
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| author | Nora Helmrich Martin Roderfeld Anne Baier Anita Windhorst Diran Herebian Ertan Mayatepek Christian Dierkes Matthias Ocker Dieter Glebe Bruno Christ Yuri Churin Karuna Irungbam Elke Roeb |
| author_facet | Nora Helmrich Martin Roderfeld Anne Baier Anita Windhorst Diran Herebian Ertan Mayatepek Christian Dierkes Matthias Ocker Dieter Glebe Bruno Christ Yuri Churin Karuna Irungbam Elke Roeb |
| author_sort | Nora Helmrich |
| collection | DOAJ |
| description | Background & Aims: The endocannabinoid system is involved in the modulation of inflammatory, fibrotic, metabolic, and carcinogenesis-associated signaling pathways via cannabinoid receptor (CB)1 and CB2. We hypothesized that the pharmacologic antagonization of CB1 receptor improves cholestasis in Abcb4-/- mice. Methods: After weaning, male Abcb4-/- mice were treated orally with rimonabant (a specific antagonist of CB1) or ACEA (an agonist of CB1) until up to 16 weeks of age. Liver tissue and serum were isolated and examined by means of serum analysis, quantitative real time polymerase chain reaction, Western blot, immunohistochemistry, and enzyme function. Untreated Abcb4-/- and Bagg Albino Mouse/c wild-type mice served as controls. Results: Cholestasis-induced symptoms such as liver damage, bile duct proliferation, and enhanced circulating bile acids were improved by CB1 antagonization. Rimonabant treatment also improved Phosphoenolpyruvat-Carboxykinase expression and reduced inflammation and the acute-phase response. The carcinogenesis-associated cellular-Jun N-terminal kinase/cellular-JUN and signal transducer and activator of transcription 3 signaling pathways activated in Abcb4-/- mice were reduced to wild-type level by CB1 antagonization. Conclusions: We showed a protective effect of oral CB1 antagonization in chronic cholestasis using the established Abcb4-/- model. Our results suggest that pharmacologic antagonization of the CB1 receptor could have a therapeutic benefit in cholestasis-associated metabolic changes, liver damage, inflammation, and carcinogenesis. |
| first_indexed | 2024-12-24T13:00:23Z |
| format | Article |
| id | doaj.art-d09d8c8611ec48a3bb15ab6b0b480739 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-24T13:00:23Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-d09d8c8611ec48a3bb15ab6b0b4807392022-12-21T16:54:10ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2022-01-0113410411055Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4-/- MiceSummaryNora Helmrich0Martin Roderfeld1Anne Baier2Anita Windhorst3Diran Herebian4Ertan Mayatepek5Christian Dierkes6Matthias Ocker7Dieter Glebe8Bruno Christ9Yuri Churin10Karuna Irungbam11Elke Roeb12Department of Gastroenterology, Giessen, GermanyDepartment of Gastroenterology, Giessen, GermanyDepartment of Gastroenterology, Giessen, GermanyInstitute for Medical Informatics, Justus Liebig University, Giessen, GermanyDepartment of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, GermanyDepartment of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, GermanyMedizinisches Versorgungszentrum for Pathology, Justus Liebig University Giessen, Trier, GermanyInstitute for Surgical Research, Philipps University of Marburg, Marburg, GermanyInstitute of Medical Virology, National Reference Centre for Hepatitis B Viruses and Hepatitis D Viruses, Justus Liebig University, Giessen, GermanyApplied Molecular Hepatology Laboratory, Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, Leipzig, GermanyDepartment of Gastroenterology, Giessen, GermanyDepartment of Gastroenterology, Giessen, GermanyDepartment of Gastroenterology, Giessen, Germany; Correspondence Address correspondence to: Elke Roeb, MD, MHAC, Department of Gastroenterology, Justus Liebig University Giessen, University Hospital Universitätsklinikum Giessen und Marburg (UKGM), Klinikstrasse 33, 35392 Giessen, Germany. fax: (49) 641-985-42339.Background & Aims: The endocannabinoid system is involved in the modulation of inflammatory, fibrotic, metabolic, and carcinogenesis-associated signaling pathways via cannabinoid receptor (CB)1 and CB2. We hypothesized that the pharmacologic antagonization of CB1 receptor improves cholestasis in Abcb4-/- mice. Methods: After weaning, male Abcb4-/- mice were treated orally with rimonabant (a specific antagonist of CB1) or ACEA (an agonist of CB1) until up to 16 weeks of age. Liver tissue and serum were isolated and examined by means of serum analysis, quantitative real time polymerase chain reaction, Western blot, immunohistochemistry, and enzyme function. Untreated Abcb4-/- and Bagg Albino Mouse/c wild-type mice served as controls. Results: Cholestasis-induced symptoms such as liver damage, bile duct proliferation, and enhanced circulating bile acids were improved by CB1 antagonization. Rimonabant treatment also improved Phosphoenolpyruvat-Carboxykinase expression and reduced inflammation and the acute-phase response. The carcinogenesis-associated cellular-Jun N-terminal kinase/cellular-JUN and signal transducer and activator of transcription 3 signaling pathways activated in Abcb4-/- mice were reduced to wild-type level by CB1 antagonization. Conclusions: We showed a protective effect of oral CB1 antagonization in chronic cholestasis using the established Abcb4-/- model. Our results suggest that pharmacologic antagonization of the CB1 receptor could have a therapeutic benefit in cholestasis-associated metabolic changes, liver damage, inflammation, and carcinogenesis.http://www.sciencedirect.com/science/article/pii/S2352345X21002630LiverRimonabantBile AcidAcute PhaseFibrosis |
| spellingShingle | Nora Helmrich Martin Roderfeld Anne Baier Anita Windhorst Diran Herebian Ertan Mayatepek Christian Dierkes Matthias Ocker Dieter Glebe Bruno Christ Yuri Churin Karuna Irungbam Elke Roeb Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4-/- MiceSummary Cellular and Molecular Gastroenterology and Hepatology Liver Rimonabant Bile Acid Acute Phase Fibrosis |
| title | Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4-/- MiceSummary |
| title_full | Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4-/- MiceSummary |
| title_fullStr | Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4-/- MiceSummary |
| title_full_unstemmed | Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4-/- MiceSummary |
| title_short | Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4-/- MiceSummary |
| title_sort | pharmacologic antagonization of cannabinoid receptor 1 improves cholestasis in abcb4 micesummary |
| topic | Liver Rimonabant Bile Acid Acute Phase Fibrosis |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X21002630 |
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