GPAT3 deficiency attenuates corticosterone-caused hepatic steatosis and oxidative stress through GSK38/Nrf2 signals

The development of nonalcoholic fatty liver disease (NAFLD) may worsen due to chronic stress or prolonged use of glucocorticoids. Glycerol-3-phosphate acyltransferase 3 (GPAT3), has a function in obesity and serves as a key rate-limiting enzyme that regulates triglyceride synthesis. However, the precise impact of GPAT3 on corticosterone (CORT)-induced NAFLD and its underlying molecular mechanism remain unclear. For our in vivo experiments, we utilized male and female mice that were GPAT3-/- and wild type (WT) and treated them with CORT for a duration of 4 weeks. In our in vitro experiments, we transfected AML12 cells with GPAT3 siRNA and subsequently treated them with CORT. Under CORT-treated conditions, the absence of GPAT3 greatly improved obesity and hepatic steatosis while enhancing the expression of genes involved in fatty acid oxidation, as evidenced by our findings. In addition, the deletion of GPAT3 significantly inhibited the production of reactive oxygen species (ROS), increased the expression of antioxidant genes, and recovered the mitochondrial membrane potential in AML12 cells treated with CORT. In terms of mechanism, the absence of GPAT3 encouraged the activation of the glycogen synthase kinase 38 (GSK38)/nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway, which served as a defense mechanism against liver fat accumulation and oxidative stress. Furthermore, GPAT3 expression was directly controlled at the transcriptional level by the glucocorticoid receptor (GR). Collectively, our findings suggest that GPAT3 deletion significantly alleviated hepatic steatosis and oxidative stress through promoting GSK38/Nrf2 signaling pathways.