15-keto-PGE2 alleviates nonalcoholic steatohepatitis through its covalent modification of NF-κB factors
Siow-Wey Hee,
Yi-Cheng Chang,
Lynn Su,
Ing-Jung Chen,
Yung-Ming Jeng,
Meng-Lun Hsieh,
Yu-Chia Chang,
Fu-An Li,
Daniel Liao,
Shiau-Mei Chen,
Lee-Ming Chuang
Affiliations
Siow-Wey Hee
Department of Internal Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan
Yi-Cheng Chang
Department of Internal Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan; Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei 100225, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan
Lynn Su
Graduate Institute of Molecular Medicine, National Taiwan University, Taipei 100225, Taiwan
Ing-Jung Chen
Graduate Institute of Molecular Medicine, National Taiwan University, Taipei 100225, Taiwan
Yung-Ming Jeng
Department of Pathology, National Taiwan University, Taipei, Taiwan; Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
Meng-Lun Hsieh
Department of Internal Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan; Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei 100225, Taiwan; Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, USA
Yu-Chia Chang
Graduate Institute of Molecular Medicine, National Taiwan University, Taipei 100225, Taiwan
Fu-An Li
Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan
Daniel Liao
Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei 100225, Taiwan
Shiau-Mei Chen
Department of Internal Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan
Lee-Ming Chuang
Department of Internal Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan; Graduate Institute of Molecular Medicine, National Taiwan University, Taipei 100225, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University, Taipei 100225, Taiwan; Corresponding author
Summary: 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.
