Ceramide kinase-mediated C1P metabolism attenuates acute liver injury by inhibiting the interaction between KEAP1 and NRF2

• Published in: Experimental & molecular medicine 2024, 56(0), , pp.946-958
• Main Authors: Dong, Wei, Li, Qing, Lu, Xing, Lan, Jianfeng, Qiu, Zhidong, Wang, Xuehong, Wang, Junnan, Zheng, Xiaojiao, Chen, Sifan, Zhang, Chong, Jin, Junfei
• Format: Article
• Language: English
• Subjects: 13/51; 14/19; 38/61; 38/77; 631/443/319/1557; 631/80/304; 64/60; 82/29; 82/51; Animals; Antioxidants; Artificial intelligence; Biomedical and Life Sciences; Biomedicine; Ceramide kinase; Ceramides - metabolism; Chemical reduction; Disease Models, Animal; Hepatocytes; Hepatocytes - metabolism; Homeostasis; Humans; Ischemia; Kelch-Like ECH-Associated Protein 1 - metabolism; Kinases; Liver diseases; Male; Medical Biochemistry; Metabolism; Mice; Molecular Docking Simulation; Molecular Medicine; NF-E2-Related Factor 2 - metabolism; Nuclear transport; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Protein Binding; Proteins; Reperfusion; Signal transduction; Stem Cells; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-024-01203-4

Acute liver injury is the basis of the pathogenesis of diverse liver diseases. However, the mechanism underlying liver injury is complex and not completely understood. In our study, we revealed that CERK, which phosphorylates ceramide to produce ceramide-1-phosphate (C1P), was the sphingolipid pathway-related protein that had the most significantly upregulated expression during acute liver injury. A functional study confirmed that CERK and C1P attenuate hepatic injury both in vitro and in vivo through antioxidant effects. Mechanistic studies have shown that CERK and C1P positively regulate the protein expression of NRF2, which is a crucial protein that helps maintain redox homeostasis. Furthermore, our results indicated that C1P disrupted the interaction between NRF2 and KEAP1 by competitively binding to KEAP1, which allowed for the nuclear translocation of NRF2. In addition, pull-down assays and molecular docking analyses revealed that C1P binds to the DGR domain of KEAP1, which allows it to maintain its interaction with NRF2. Importantly, these findings were verified in human primary hepatocytes and a mouse model of hepatic ischemia‒reperfusion injury. Taken together, our findings demonstrated that CERK-mediated C1P metabolism attenuates acute liver injury via the binding of C1P to the DGR domain of KEAP1 and subsequently the release and nuclear translocation of NRF2, which activates the transcription of cytoprotective and antioxidant genes. Our study suggested that the upregulation of CERK and C1P expression may serve as a potential antioxidant strategy to alleviate acute liver injury. NRF2 activation: C1P’s path to redox homeostasis success Liver diseases are a major worldwide health problem, and the exact causes of sudden liver damage are not completely known. Scientists discovered that a protein called Ceramide Kinase (CERK) and its product Ceramide-1-Phosphate (C1P) are vital in safeguarding the liver from harm. The research, led by Wei Dong and his team, revealed that CERK and C1P trigger a crucial protective process in the liver, known as the NRF2-KEAP1 signaling pathway. This process helps keep a balance of oxidation and reduction reactions in the liver, shielding it from harm. The scientists discovered that C1P attaches to a protein named KEAP1, which enables another protein, NRF2, to enter the cell’s core and trigger the protective process. This study could pave the way for new liver disease treatments. This summary was initially drafted using