Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction.
Elife
; 102021 02 22.
Article
em En
| MEDLINE
| ID: mdl-33616039
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sepse
/
Hepatócitos
/
Ácido Dicloroacético
/
Mitocôndrias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article