Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction
| Title: | Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction |
|---|---|
| Authors: | Rabina Mainali, Manal Zabalawi, David Long, Nancy Buechler, Ellen Quillen, Chia-Chi Key, Xuewei Zhu, John S Parks, Cristina Furdui, Peter W Stacpoole, Jennifer Martinez, Charles E McCall, Matthew A Quinn |
| Source: | eLife, Vol 10 (2021) |
| Publisher Information: | eLife Sciences Publications Ltd, 2021. |
| Publication Year: | 2021 |
| Collection: | LCC:Medicine LCC:Science LCC:Biology (General) |
| Subject Terms: | sepsis, liver, inflammation, metabolism, steatosis, Medicine, Science, Biology (General), QH301-705.5 |
| More Details: | Metabolic reprogramming between resistance and tolerance occurs within the immune system in response to sepsis. While metabolic tissues such as the liver are subjected to damage during sepsis, how their metabolic and energy reprogramming ensures survival is unclear. Employing comprehensive metabolomic, lipidomic, and transcriptional profiling in a mouse model of sepsis, we show that hepatocyte lipid metabolism, mitochondrial tricarboxylic acid (TCA) energetics, and redox balance are significantly reprogrammed 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. Transcriptomic analysis of liver tissue supports and extends the hepatocyte findings. Strikingly, the administration of the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate reverses dysregulated hepatocyte metabolism and mitochondrial dysfunction. In summary, our data indicate that sepsis promotes hepatic metabolic dysfunction and that targeting the mitochondrial PDC/PDK energy homeostat rebalances transcriptional and metabolic manifestations of sepsis within the liver. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2050-084X |
| Relation: | https://elifesciences.org/articles/64611; https://doaj.org/toc/2050-084X |
| DOI: | 10.7554/eLife.64611 |
| Access URL: | https://doaj.org/article/54dd853ae26241009d6cb06d0d6d3a95 |
| Accession Number: | edsdoj.54dd853ae26241009d6cb06d0d6d3a95 |
| Database: | Directory of Open Access Journals |
| ISSN: | 2050084X |
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| DOI: | 10.7554/eLife.64611 |
| Published in: | eLife |
| Language: | English |