Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction
- Wake Forest School of Medicine, United States
- University of Florida School of Medicine, United States
- National Institute of Environmental Health Sciences, United States
Abstract
Metabolic reprogramming between resistance and tolerance occurs within the immune system in response to sepsis. While metabolic tissues such as the liver are subject 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 TCA energetics, and redox balance are significantly reprogramed 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 (DCA) reverses dysregulated hepatocyte metabolism and mitochondrial dysfunction. In summary, our data indicate sepsis promotes hepatic metabolic dysfunction and that targeting the mitochondrial PDC/PDK energy homeostat rebalances transcriptional and metabolic manifestations of sepsis within the liver.
Data availability
Sequencing data have been deposited in GEO under accession code GSE167127
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Effects of sepsis and dichloroacetate on hepatic transcriptomeNCBI Gene Expression Omnibus, GSE167127.
Article and author information
Author details
Funding
National Institute of Environmental Health Sciences (1ZIAES10328601)
- Jennifer Martinez
National Heart, Lung, and Blood Institute (R01 HL132035)
- Xuewei Zhu
National Institute of Diabetes and Digestive and Kidney Diseases (K01 DK117069)
- Chia-Chi Key
National Institute on Aging (K01 AG056663)
- Ellen Quillen
National Institute of Allergy and Infectious Diseases (R01 AI065791)
- Charles E McCall
National Institute of General Medical Sciences (R01 GM102497)
- Charles E McCall
National Institute of General Medical Sciences (R35 GM126922)
- Charles E McCall
National Heart, Lung, and Blood Institute (R01 HL119962)
- John S Parks
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (A19-097) Wake Forest School of Medicine.
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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