Transplantation of brown adipose tissue up-regulates miR-99a to ameliorate liver metabolic disorders in diabetic mice by targeting NOX4

ABSTRACT Nonalcoholic fatty liver disease (NAFLD), main cause of liver damage, is inextricably linked to diabetes. However, there is no specific means to improve the pathology of fatty liver in diabetic patients. Brown adipose tissue (BAT) is an important endocrine organ that secretes adipokines and microRNAs (miRNAs) involved in systemic metabolic regulation. To investigate the effects of BAT transplantation on liver lipid metabolism in diabetic mice, we transplanted BAT from male donor mice into diabetic mice induced by streptozotocin (STZ) combined with high-fat diet (HFD). At 10 weeks after transplantation, BAT transplantation significantly decreased the blood glucose and lipid, downregulated FAS, CD36, Scd1, ACCα, NOX2, NOX4, TGF-β1, FN and COL-1, up-regulated Nrf2, reversed the pathological changes of liver and increased the circulating miR-99a in diabetic mice. To verify whether circulating miR-99a improves oxidative stress by targeting inhibition of NOX4, we used 0.4mM palmitic acid (PA) to treat the LO2 cells. The expression of NOX4 protein was significantly decreased after transfection with miR-99a mimic, and increased after transfection with miR-99a inhibitor. Luciferase reporter assay confirmed that miR-99a could target NOX4 mRNA. These findings clarify the role of miR-99a and NOX4 in liver beneficial effect of BAT transplantation in diabetic mice