Nuclear factor erythroid 2‐related factor 2 ameliorates disordered glucose and lipid metabolism in liver: Involvement of gasdermin D in regulating pyroptosis

Abstract

Abstract Background The epidemic of metabolic dysfunction‐associated fatty liver disease linked to excessive high‐fat diet (HFD) consumption has sparked widespread public concern. Nuclear factor erythroid 2‐related factor 2 (NRF2) has been reported to improve glucose/lipid metabolism, liver lipid degeneration and alleviate HFD‐induced inflammation. However, its pathways and mechanisms of action are not fully understood. Methods To confirm the effect of NRF2 on glucose/lipid metabolism in the liver, Nrf2‐/‐ mice as well as liver‐specific Nrf2 knockout mice, and AAV‐TBG‐Nrf2 were employed. The hyperinsulinemic‐euglycemic clamp was utilized to determine the effect of NRF2 on glucose metabolism. To elucidate the effect of NRF2 on pyroptosis, we performed western blots, immunofluorescence, quantitative real‐time PCR, and Flow cytometry experiments. Finally, chromatin immunoprecipitation‐seq and dual‐luciferase reporter assay was used to underscore the transcriptional regulatory effect of NRF2 on Gsdmd. Results We found that overexpression of Nrf2 inhibited the expression of inflammatory cytokines and pyroptosis markers, including cle‐Caspase1, NLRP3 and the N‐terminus of gasdermin D (N‐GSDMD) both in vivo and in vitro, while Nrf2 deficiency was the opposite. Specifically, with NRF2 expression up‐regulated, GSDMD expression decreased and Gsdmd overexpression partially reversed the effect of Nrf2 overexpression on pro‐inflammatory phenotype. Mechanistically, we demonstrate that NRF2 binds to the Gsdmd promoter at the −2110 ‐ 1130 bp site, inhibiting the GSDMD expression and thereby improving glucose/lipid metabolism and liver steatosis. Conclusion Our data indicate that NRF2 is an effective inhibitor of pyroptosis and has a multi‐target effect in the treatment of obesity‐related metabolic diseases. Key points MAFLD is associated with increased hepatocytes NRF2 expression. NRF2 alleviates MAFLD by suppressing pyroptosis. NRF2 directly inhibits GSDMD expression to regulate pyroptosis. Targeting the NRF2–pyroptosis (GSDMD) axis offers a potential therapeutic strategy for MAFLD.

Keywords

• glucose/lipid metabolism
• GSDMD
• NRF2
• pyroptosis