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

Abstract

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.

Graphical abstract