Osteocalcin improves nonalcoholic fatty liver disease in mice through activation of Nrf2 and inhibition of JNK

Recent studies have demonstrated a protective effect of osteocalcin against nonalcoholic fatty liver disease (NAFLD), although the specific underlying mechanisms remain unclear. Nrf2 and JNK pathways play important roles in the pathogenesis of NAFLD. The present study aimed to investigate whether osteocalcin protects against NAFLD by regulating these pathways. Male C57/BL6J mice were fed a high-fat diet for 12 weeks to induce NAFLD and were treated with recombinant decarboxylate osteocalcin (30 ng/g) or vehicle by daily intraperitoneal injection during this period. Osteocalcin treatment protected mice from diet-induced hepatic triglyceride accumulation and liver injury. Increased levels of malondialdehyde and 8-iso-prostaglandin F2 alpha as well as a higher ratio of oxidized to reduced glutathione in the liver of mice fed a high-fat diet were significantly decreased due to the intervention of osteocalcin. Osteocalcin treatment not only activated Nrf2 nuclear translocation and up-regulated the expression of antioxidant enzyme genes (catalase, SOD, and GPx), but also inhibited the activation of JNK in the liver. GPRC6A, the putative receptor of osteocalcin, was found in the liver. In conclusion, these results suggest that osteocalcin improves NAFLD by activating the Nrf2 pathway to alleviate oxidative stress and inhibiting JNK pathway.