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

doi:10.1016/j.isci.2023.107997

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

iScience. 2023 Sep 22;26(10):107997. doi: 10.1016/j.isci.2023.107997. eCollection 2023 Oct 20.

Authors

Siow-Wey Hee¹, Yi-Cheng Chang^{1

2

3}, Lynn Su⁴, Ing-Jung Chen⁴, Yung-Ming Jeng^{5

6

7}, Meng-Lun Hsieh^{1

2

8}, Yu-Chia Chang⁴, Fu-An Li³, Daniel Liao², Shiau-Mei Chen¹, Lee-Ming Chuang^{1

4

9}

Affiliations

¹ Department of Internal Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan.
² Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei 100225, Taiwan.
³ Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan.
⁴ Graduate Institute of Molecular Medicine, National Taiwan University, Taipei 100225, Taiwan.
⁵ Department of Pathology, National Taiwan University, Taipei, Taiwan.
⁶ Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
⁷ Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁸ Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, USA.
⁹ Graduate Institute of Clinical Medicine, National Taiwan University, Taipei 100225, Taiwan.

Abstract

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.

Keywords: Cognitive neuroscience; Machine learning.