A novel RELA K119 deacetylation mediated by SIRT7 is a pivotal activator to exacerbate liver inflammation and fibrosis in teleosts

Abstract Post-translational modifications (PTMs) regulate the activity and functionality of RELA, but their role in the pathogenesis of liver fibrosis is unclear. This study was performed to understand the regulation mechanism of acetylation of RELA on liver inflammation and fibrosis in a model animal of innate glucose intolerance, largemouth bass, and to provide a potential target and biomarker for liver fibrosis therapy. We found that the acetylation of total proteins and RELA was significantly reduced in fibrotic livers of largemouth bass induced by a high-carbohydrate and high-fat diet (HCHFD) and CCL4 challenge. Furthermore, quantitative acetylome data showed that the K119 site of RELA was deacetylated in fibrotic livers compared to healthy controls. Subsequently, we reveal a new mechanism that SIRT7 deacetylates RELA at the K119 site in largemouth bass. RELA K119 deacetylation enhances RELA transcriptional activity by increasing its DNA-binding activity, and facilitates nuclear translocation of RELA, resulting in the overwhelming release of proinflammatory factors, and subsequently enhancing liver inflammation and fibrosis. Pharmacological inhibition of SIRT7 using a specific inhibitor restores the decreased acetylation of RELA in vivo and in vitro, and reduces the transcriptional activity, nuclear localization of RELA and the expression of its target genes, which ultimately attenuates liver inflammation and fibrosis. These findings uncover a novel mechanism underlying liver fibrosis involving SIRT7-mediated deacetylation of RELA to activate the proinflammatory gene program, and thus provide important insights and biomarkers into the effective strategies for limiting liver inflammation and fibrosis.