Cannabinoid receptor type 1 antagonist inhibits progression of obesity‐associated nonalcoholic steatohepatitis in a mouse model by remodulating immune system disturbances

SCOPE: This study investigated whether AM251, a cannabinoid receptor type 1 (CB1) antagonist, ameliorates hepatic levels of metabolic abnormalities and inflammatory responses in a murine nonalcoholic steatohepatitis (NASH) model via reversal of disturbances in the immune system. METHODS AND RESULTS: Fifteen‐week‐old male obese db/db mice were randomly assigned to the following two groups: no treatment and treatment with AM251 at 5 mg/kg for 15 days. C57BL/6J‐Lean mice were utilized as the control group. Plasma parameters, liver histopathology, and hepatic status were measured. For the in vitro study, macrophage‐derived RAW264.7 cells were cultured with AM251 or CB1 small interfering RNA (siRNA) before challenge with arachidonyl‐2′‐chloroethylamide (ACEA) or a high concentration of fatty acids (HFFAs). The db/db mice exhibited an increase in CB1 levels, lipid droplet accumulation, mitogen‐activated protein kinase‐related inflammatory responses, and macrophage and neutrophil infiltration in the liver tissues. Flow cytometry analysis revealed an elevation in macrophages and T helper cells, plus a decrease in natural killer T cells and regulatory T cells in the liver tissues of the db/db mice; treatment with 5 mg/kg AM251 reversed these changes. Moreover, in vitro experiments revealed that administration of 3.3 μM AM251 or CB1 siRNA prevented 1 mM HFFA‐ and 1 μΜ ACEA‐induced inflammatory cytokine protein expression in the RAW264.7 cells. CONCLUSION: These findings suggested that a blockade caused by CB1 reduced obesity‐associated NASH progression via correction of immune system dysregulations and elevated inflammatory responses in the liver tissues.