Cannabinoid 2 Receptor Activation Mitigates High-Fat Diet/Streptozotocin-Induced Nonalcoholic Fatty Liver Disease in Diabetic Mice by Modulation of Oxidative Stress, Inflammation, and Fibrosis.

Nonalcoholic fatty liver disease (NAFLD) represents one of the multifactorial complications of type 2 diabetes (T2D). The cannabinoid type 2 receptor (CB2R) plays a role in diabetes and diabetic complications; therefore, the aim of the present study was to investigate the role of β-caryophyllene (BCP), a CB2R agonist, in NAFLD associated with T2D and underlying CB2R-mediated pharmacological and molecular mechanisms. The murine model of T2D was developed by feeding male C57BL/6 J mice a high-fat diet along with streptozotocin (STZ) injections. After developing diabetes, the animals were orally administered BCP (50 mg/kg, p.o.) for 12 weeks. Treatment with BCP reduced the elevation of liver injury markers and inhibited the expression of NADPH oxidase 2 and NADPH oxidase 4, activating Nrf2 signaling and showing liver protective effects and mitigation of oxidative stress. BCP treatment also inhibited hepatic inflammation, as shown by inhibition of NOD-like receptor protein 3 inflammasome activation in T2D mice. Furthermore, treatment with BCP suppressed hepatic fibrosis and endothelial-to-mesenchymal transition by inhibiting transforming growth factor-β/suppressor of mothers against decapentaplegic (Smad) signaling. Taken together, BCP appears to efficiently improve liver function in diabetic mice by suppressing pathologic events of oxidative stress, inflammation, and fibrosis. To reveal the CB2R-dependent mechanism of BCP, the diabetic animals were pretreated with a CB2R antagonist, AM630, which is expected to abrogate the protective effects of BCP. Pretreatment with AM630 abolished the beneficial effects of BCP on hepatic oxidative stress, inflammation, and fibrosis, as well as liver function in T2D mice. These results demonstrate that BCP has the potential to be a novel agent of natural origin from cannabinoids, like compounds, for NAFLD associated with diabetes. The study is suggestive of therapeutic benefits of BCP and could be useful in nutraceutical and pharmaceutical development of BCP and a new in-class agent mediating CB2R activation for NAFLD with diabetes.