Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4 Mice

Abstract

Antagonization of endocannabinoid receptor 1 by rimonabant ameliorated metabolic, inflammatory, and carcinogenesis-associated processes, as well as serum bile acids in Abcb4-knockout mice. This leads to an improvement of cholestasis and reduced hepatic pathogenesis. 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 Q10 . Liver tissue and serum were isolated and examined by means of serum analysis, quantitative reverse-transcription polymerase chain reaction Q11 , Western blot, immunohistochemistry, and enzyme function. Untreated Abcb4 -/and BALB/ Q12 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 PEPCK Q13 expression and reduced inflammation and the acute-phase response. The carcinogenesis-associated c-Jun N-terminal kinase/c-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.

Hypolipidemic and Anti‐Obesity Effect of Anserine on Mice Orally Administered with High‐Fat Diet via Regulating SREBP‐1, NLRP3, and UCP‐1

“…These experimental results suggested that inhibiting SREBP-1 protein expression in the liver was an important measure to suppress obesity. [32] Excessive LDL-C content can cause damage to vascular endothelial cells, which causes lipid accumulation in blood vessels and leads to atherosclerosis. [33] Therefore, inhibiting LDL-C content is an important measure to reduce blood lipids.…”

“…These experimental results suggested that inhibiting SREBP‐1 protein expression in the liver was an important measure to suppress obesity. [ 32 ]…”