Exogenous hydrogen sulfide alleviates hepatic endoplasmic reticulum stress via SIRT1/FoxO1/PCSK9 pathway in NAFLD

High-fat-induced endoplasmic reticulum (ER) stress has been the main reason for the occurrence and development of nonalcoholic fatty liver disease (NAFLD). Hydrogen sulfide (H₂ S) produces a marked effect on regulating lipid metabolism and antioxidation, whose effects on ER stress of NAFLD are still unclear. Here, we studied the influence of exogenous H₂ S on NAFLD and its potential mechanism. In vivo, NAFLD model was induced by high-fat diet (HFD) for 12 weeks, followed by intraperitoneal injection of exogenous H₂ S intervention for 4 weeks. HepG2 cells exposure to lipid mixture (LM) were used as vitro model to explore the potential mechanism. We found exogenous H₂ S significantly inhibited the hepatic ER stress and improved the liver fat deposition of HFD-fed mice. These similar results were also observed in HepG2 cells dealt with LM after exogenous H₂ S treatment. Further mechanism studies showed exogenous H₂ S strengthened the combination of FoxO1 with the PCSK9 promoter gene through SIRT1-mediated deacetylation, thereby inhibiting the PCSK9 expression to relieve the hepatic ER stress. However, SIRT1 knockout eliminated the effects of exogenous H₂ S on FoxO1 deacetylation, PCSK9 inhibition, and remission of hepatic ER stress and steatosis. In conclusion, exogenous H₂ S improved NAFLD by inhibiting hepatic ER stress through SIRT1/FoxO1/PCSK9 pathway. Exogenous H₂ S and ER stress may be potential drug and target for the treatment of NAFLD, respectively.