دورية أكاديمية
SIRT1 regulates hepatocyte programmed cell death via GSDME - IL18 axis in human and mouse liver transplantation
| العنوان: | SIRT1 regulates hepatocyte programmed cell death via GSDME - IL18 axis in human and mouse liver transplantation |
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| المؤلفون: | Kadono, Kentaro, Kojima, Hidenobu, Yao, Siyuan, Kageyama, Shoichi, Nakamura, Kojiro, Hirao, Hirofumi, Ito, Takahiro, Dery, Kenneth J., Farmer, Douglas G., Kaldas, Fady M., Li, Xiaoling, Kupiec-Weglinski, Jerzy W. |
| المساهمون: | U.S. Department of Health & Human Services | NIH | Center for Scientific Review, U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences |
| المصدر: | Cell Death & Disease ; volume 14, issue 11 ; ISSN 2041-4889 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Cancer Research, Cell Biology, Cellular and Molecular Neuroscience, Immunology |
| الوصف: | Sirtuin 1 (SIRT1) is a histone/protein deacetylase in the cellular response to inflammatory, metabolic, and oxidative stressors. We previously reported that myeloid SIRT1 regulates the inflamed liver’s canonical pyroptosis cell death pathway. However, whether/how hepatocyte SIRT1 is engaged in programmed cell death in the cold-stressed liver remains uncertain. Here, we undertook translational studies in human and mouse orthotopic liver transplantation (OLT) to interrogate the significance of hepatocyte-specific SIRT1 in cold-stored donor livers and liver grafts after reperfusion. In the clinical arm of sixty human OLT patients, hepatic SIRT1 levels in cold-preserved donor livers correlated with the anti-apoptotic Bcl-2 expression. After reperfusion, improved OLT function was accompanied by hepatic SIRT1 levels negatively associated with cleaved caspase-3 expression. In the experimental arm, we compared FLOX-control with hepatocyte-specific SIRT1-KO livers after orthotopic transplantation into WT mouse recipients, parallel with primary murine hepatocyte cultures subjected to cold activation with/without knockdown of SIRT1, GSDME, and IL18Rβ. Indeed, hepatocyte SIRT1 deficiency upregulated apoptosis and GSDME-mediated programmed cell death, deteriorating hepatocellular function and shortening OLT survival. Augmented GSDME processing, accompanied by increased secretion of IL18 by stressed hepatocytes, was prominent in SIRT1-deficient, cold-stored livers. Hepatocyte SIRT1 expression regulated anti-apoptotic Bcl-2/XIAP proteins, suppressed cold stress-triggered apoptosis, and mitigated GSDME licensing to release IL18. Notably, consistent with the ability of IL18 to depress hepatocyte SIRT1 and Bcl-2/XIAP in vitro, IL18 neutralization in vivo prevented hepatocellular damage and restored the anti-apoptotic phenotype in otherwise injury-prone SIRT1-deficient OLTs. In conclusion, this translational study identifies a novel hepatocyte SIRT1-IL18 molecular circuit as a therapeutic target in the mechanism ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41419-023-06221-0 |
| الإتاحة: | https://doi.org/10.1038/s41419-023-06221-0Test https://www.nature.com/articles/s41419-023-06221-0.pdfTest https://www.nature.com/articles/s41419-023-06221-0Test |
| حقوق: | https://creativecommons.org/licenses/by/4.0Test ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: | edsbas.16F5D660 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41419-023-06221-0 |
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