Hepatic ischemia-reperfusion injury (IRI) is a common and unavoidable complication associated with liver transplants that may result in impaired liver function or even post-transplant liver failure. Although various mechanisms have been implicated in the pathogenesis and progression of hepatic IRI, the characteristic alterations occurring at the transcriptome and metabolic levels remain to be investigated.

In this study, published in the Genes and Diseases journal, researchers from Chongqing Medical University employed transcriptomics and metabolomics analyses to identify the differentially expressed genes and metabolites during the early, intermediate, and late phases of hepatic IRI in a mouse model.

Mouse livers subjected to reperfusion for 12 hrs, 24 hrs, and 48 hrs (corresponding to early, intermediate, and late stages) following 1 hr-ischemia were used for further analysis. Transcriptome data analysis revealed that 1115 differentially expressed genes were co-expressed between the three groups. KEGG and GO analysis revealed the enrichment of glucose and carbohydrate metabolic pathways in early IRI, enrichment of glucose/lipid metabolic pathways and activation of the inflammatory pathway in intermediate IRI, and the enrichment of the lipid metabolic pathways during the late phase of IRI. These results were further validated with Western blotting and qRT-PCR, which revealed the activation of the PI3K/AKT/mTOR pathway.
Metabolomics analysis showed that primary metabolic characteristics of lipid metabolism were altered in the early, intermediate, and late phases of IRI. Furthermore, quantification of free fatty acids in the mouse liver tissues showed a significant decrease in the IR12 and IR24 groups, suggesting a disorder in lipid metabolism.

In conclusion, the key findings of this study show that i) intermediate IRI is characterized by an inflammatory disorder triggered by the overproduction of ROS and the release of DAMPs and pro-inflammatory cytokines, which aggravate apoptosis and hepatocyte damage, ii) the marked upregulation of the PI3K-AKT and HIF-1 pathways in the intermediate phase serves as an adaptive response in regulating anaerobic glycolysis and the inflammatory response to improve IRI, and iii) the glycolysis/gluconeogenesis pathway is altered exclusively during the early phase of IRI. The authors suggest therapeutic interventions targeting glucose and lipid metabolism reprogramming pathways may help mitigate hepatic IRI.

Reference

Title of the original paper: Multi-time point transcriptomics and metabolomics reveal key transcription and metabolic features of hepatic ischemia-reperfusion injury in mice

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2024.101465

Funding information:

National Natural Science Foundation of China (No. 82300745)
China Postdoctoral Science Foundation (No. 2023M730442)
Chongqing Postdoctoral Science Foundation of China (No. CSTB2023NSCQ-BHX1003)
Postdoctoral Cultivation Project of the First Affiliated Hospital of Chongqing Medical University (No.CYYY-BSHPYXM-202301)
Chongqing Postdoctoral Innovation Talents Support Program (Chongqing, China) (No. 2309013437264551)

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