Dichloroacetate improves hepatic and systemic energy metabolism during sepsis

Dramatic metabolic reprogramming between an anabolic resistance and catabolic tolerance 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 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, elevated triglyceride synthesis, and lipid droplet accumulation in the septic hepatocytes. Transcription analysis of liver tissue supports and extends the hepatocyte findings. Plasma metabolomics show systemic hypoglycemia and increased concentrations of free fatty acids, ketones and corticosterone in parallel with liver reprogramming. Strikingly, the administration of the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate (DCA) reverses dysregulated hepatocyte and systemic metabolism and mitochondrial dysfunction. DCA administered during sepsis arrests anorexia and weight loss, restores V02 levels as an index of increased carbohydrate oxidation and promotes physical activity. We suggest that sepsis inflicts an energy demand and supply crisis with distinct shifts in hepatocyte and systemic mitochondrial function. Targeting the mitochondrial PDC/PDK energy homeostat rebalances life-threatening energy deregulation caused by bacterial sepsis.