Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction
| Autor: | Xuewei Zhu, Cristina M. Furdui, Matthew A. Quinn, Peter W. Stacpoole, Ellen E. Quillen, Nancy L. Buechler, John S. Parks, Charles E. McCall, Jennifer Martinez, Manal Zabalawi, David L. Long, Rabina Mainali, Chia-Chi C. Key |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Mouse Anabolism Pharmacology sepsis Mice 0302 clinical medicine Immunology and Inflammation steatosis Biology (General) Chemistry Kinase General Neuroscience General Medicine Mitochondria medicine.anatomical_structure 030220 oncology & carcinogenesis Hepatocyte Medicine medicine.symptom Oxidation-Reduction Research Article Pyruvate dehydrogenase kinase QH301-705.5 Science Citric Acid Cycle Inflammation liver General Biochemistry Genetics and Molecular Biology Sepsis 03 medical and health sciences medicine Animals General Immunology and Microbiology Dichloroacetic Acid Septic shock Catabolism business.industry Pyruvate Dehydrogenase Acetyl-Transferring Kinase Lipid metabolism Metabolism medicine.disease Mice Inbred C57BL Citric acid cycle Disease Models Animal 030104 developmental biology inflammation Hepatocytes Steatosis Energy Metabolism business metabolism |
| Zdroj: | eLife, Vol 10 (2021) eLife |
| Popis: | Dramatic metabolic reprogramming between an anabolic resistance and catabolic tol-erance state occurs within the immune system in response to systemic infection with the sepsis syndrome. While metabolic tissues such as the liver are subject to end-organ damage during sepsis and are the primary cause of sepsis death, how their metabolic and energy reprogramming during sepsis state ensures survival is unclear. Employing comprehensive metabolomic screening, targeted lipidomic screening, and transcriptional profiling in a mouse model of septic shock, we show that hepatocyte li-pid metabolism, mitochondrial TCA energetics, and redox balance are significantly re-programed after cecal ligation and puncture (CLP). We identify increases in TCA cycle metabolites citrate, cis-aconitate, and itaconate with reduced fumarate and triglyceride accumulation in septic hepatocytes. Transcription analysis of liver tissue supports and extends the hepatocyte findings. Strikingly, the administration of the pyruvate dehy-drogenase kinase (PDK) inhibitor dichloroacetate (DCA) reverses dysregulated hepatocyte metabolism and mitochondrial dysfunction. Our data indicate sepsis pro-motes hepatic metabolic dysfunction. Furthermore, our data indicate that targeting the mitochondrial PDC/PDK energy homeostat rebalances transcriptional and metabolic manifestations of sepsis within the liver. ### Competing Interest Statement The authors have declared no competing interest. |
| Databáze: | OpenAIRE |
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