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 (H2S) 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 H2S 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 H2S intervention for 4 weeks. HepG2 cells exposure to lipid mixture (LM) were used as vitro model to explore the potential mechanism. We found exogenous H2S 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 H2S treatment. Further mechanism studies showed exogenous H2S 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 H2S on FoxO1 deacetylation, PCSK9 inhibition, and remission of hepatic ER stress and steatosis. In conclusion, exogenous H2S improved NAFLD by inhibiting hepatic ER stress through SIRT1/FoxO1/PCSK9 pathway. Exogenous H2S and ER stress may be potential drug and target for the treatment of NAFLD, respectively. Whether exogenous hydrogen sulfide (H2S) protects nonalcoholic fatty liver disease (NAFLD) by suppressing endoplasmic reticulum (ER) stress and its specific mechanism is still unclear. Our study clarified exogenous H2S inhibited PCSK9 in a SIRT1/FoxO1‐dependent manner, thereby mitigating the hepatic ER stress to improve NAFLD. SIRT1/FoxO1 was probably a novel signaling pathway to regulate PCSK9, and inhibition of PCSK9 can be a new therapeutic target for NAFLD, which exogenous H2S had been proved to possess these effects through our experiments.