Role of hepatocyte-specific FOXO1 in hepatic glucolipid metabolic disorders induced by perfluorooctane sulfonate

Abstract

Perfluorooctane sulfonate (PFOS), a prevalent perfluoroalkyl substance (PFAS), is widely present in various environmental media, animals, and even human bodies. It primarily accumulates in the liver, contributing to the disruption of hepatic metabolic homeostasis. However, the precise mechanism underlying PFOS-induced hepatic glucolipid metabolic disorders remains elusive. The transcription factor forkhead box protein O 1 (FOXO1) plays a crucial role in regulating hepatic glucolipid metabolism; however, its involvement in PFOS-induced hepatic glucolipid metabolic disorders has not been thoroughly explored. Molecular docking revealed high binding affinity between PFOS and FOXO1. Male C57BL/6 mice were exposed to PFOS at doses of 0.3, 1.0, and 3.0 mg/kg body weight for 12 weeks to assess its subchronic effects on hepatic glucolipid metabolism in this work. The results indicate that PFOS exposure increases hepatic acetylated FOXO1 expression, promotes liver lipid accumulation, suppresses gluconeogenesis, whereas fasting blood glucose levels remain unaffected but this dysregulation results in insulin resistance. Furthermore, hepatic deletion of FOXO1 in PFOS-exposed mice ameliorates liver injury and reduces lipid accumulation by suppressing hepatic autophagy without significantly affecting gluconeogenesis. In conclusion, FOXO1 may play a pivotal role in the development of PFOS-induced hepatic glucolipid metabolic disorder.