15-keto-PGE2 alleviates nonalcoholic steatohepatitis through its covalent modification of NF-κB factors

• Published in: iScience Vol. 26; no. 10; p. 107997
• Main Authors: Hee, Siow-Wey, Chang, Yi-Cheng, Su, Lynn, Chen, Ing-Jung, Jeng, Yung-Ming, Hsieh, Meng-Lun, Chang, Yu-Chia, Li, Fu-An, Liao, Daniel, Chen, Shiau-Mei, Chuang, Lee-Ming
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 20.10.2023; Elsevier
• Subjects: Cognitive neuroscience; Machine learning; Cognitive neuroscience; Machine learning
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.107997

15-keto-PGE2 is one of the eicosanoids with anti-inflammatory properties. In this study, we demonstrated that 15-keto-PGE2 post-translationally modified the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) subunits p105/p50 and p65 at Cys59 and Cys120 sites, respectively, hence inhibiting the activation of NF-κB signaling in macrophages. In mice fed a high-fat and high-sucrose diet (HFHSD), 15-keto-PGE2 treatment reduced pro-inflammatory cytokines and fasting glucose levels. In mice with non-alcoholic steatohepatitis (NASH) induced by a prolonged HFHSD, 15-keto-PGE2 treatment significantly decreased liver inflammation, lowered serum levels of alanine transaminase (ALT) and aspartate transferase (AST), and inhibited macrophage infiltration. It also reduced lipid droplet size and downregulated key regulators of lipogenesis. These findings highlight the potential of 15-keto-PGE2, through NF-κB modification, in preventing the development and progression of steatohepatitis, emphasizing the significance of endogenous lipid mediators in the inflammatory response. [Display omitted] •15-keto-PGE2 inhibits NF-κB signaling in macrophages•15-keto-PGE2 post-translationally modified NF-κB subunits•15-keto-PGE2 reduces pro-inflammatory cytokines on a high-fat, high-sucrose diet•15-keto-PGE2 decreases steatohepatitis in NASH mice Cognitive neuroscience; Machine learning