Alternative splicing of CEACAM1 by hypoxia-inducible factor–1α enhances tolerance to hepatic ischemia in mice and humans

• DOI: 10.1126/scitranslmed.adf2059
• Publication Date: 2023-08-02T17:58:55Z
• Authors: Kenneth J. Dery; Hidenobu Kojima; Shoichi Kageyama; Kentaro Kadono; Hirofumi Hirao; Brian Cheng; Yuan Zhai; Douglas G. Farmer; Fady M. Kaldas; Xiaoyi Yuan; Holger K. Eltzschig; Jerzy W. Kupiec-W...
• Keywords: 570; Medical Sciences; 610; alpha Subunit; Biomedical Informatics; Mice; 03 medical and health sciences; Ischemia; Medical Specialties; Medicine and Health Sciences; Living Donors; and Immunity; Humans; Animals; Biological Phenomena; 0303 health sciences; Cell Phenomena; Liver Diseases; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Transplantation; Alternative Splicing; Oncology; Medical Microbiology; Medical Molecular Biology; Hypoxia-Inducible Factor 1; Cell Adhesion Molecules

Although alternative splicing (AS) drives transcriptional responses and cellular adaptation to environmental stresses, its contributions in organ transplantation have not been appreciated. We shown that carcinoembryonic antigen–related cell adhesion molecule (Ceacam1; CD66a ), a transmembrane biliary glycoprotein expressed epithelial, endothelial, immune cells, determines donor liver transplant quality. Here, we studied how AS of Ceacam1 affects ischemia-reperfusion injury (IRI) mouse human livers. found the short cytoplasmic isoform Ceacam1-S increased during early acute late resolution phases warm IRI mice. Transfection Ceacam1-deficient hepatocytes with adenoviral mitigated hypoxia-induced loss by repressing Ask1/p-p38 death pathway. Nucleic acid–blocking morpholinos, designed selectively induce Ceacam1-S, protected hepatocyte cultures against temperature-induced stress vitro. Luciferase chromatin immunoprecipitation assays identified direct binding hypoxia-inducible factor–1α (Hif-1α) polypyrimidine tract protein 1 ( Ptbp1 ) promoter region. Dimethyloxalylglycine livers from IR hepatocellular damage inhibiting prolyl hydroxylase domain–containing promoting . Last, analysis 46 grafts revealed CEACAM1-S positively correlated pretransplant HIF1A expression. This also better outcomes, including reduced TIMP1 , total bilirubin, proinflammatory MCP1 CXCL10 cytokines, activation markers IL17A incidence delayed complications anastomosis. translational study Hif-1α–controlled through regulation region, as functional underpinning hepatoprotection tissue transplantation.