Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4-/- MiceSummary

Cellular and Molecular Gastroenterology and Hepatology

Bruno Christ¹  Martin Roderfeld²  Yuri Churin²  Anne Baier²  Elke Roeb²  Nora Helmrich²  Karuna Irungbam²  Ertan Mayatepek³  Diran Herebian³  Anita Windhorst⁴  Matthias Ocker⁵  Dieter Glebe⁶  Christian Dierkes⁷ 

[1] Applied Molecular Hepatology Laboratory, Department of Visceral, Transplant, Thoracic and Vascular Surgery, University of Leipzig Medical Center, Leipzig, Germany;Department of Gastroenterology, Giessen, Germany;Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany;Institute for Medical Informatics, Justus Liebig University, Giessen, Germany;Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany;Institute of Medical Virology, National Reference Centre for Hepatitis B Viruses and Hepatitis D Viruses, Justus Liebig University, Giessen, Germany;Medizinisches Versorgungszentrum for Pathology, Justus Liebig University Giessen, Trier, Germany;

关键词: Liver;    Rimonabant;    Bile Acid;    Acute Phase;    Fibrosis;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown