Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction

Area of Science:

• Immunology
• Metabolic disorders
• Hepatology

Background:

• Sepsis triggers metabolic shifts in immune cells, but liver reprogramming for survival remains unclear.
• Liver damage is common in sepsis, impacting overall patient outcomes.
• Understanding hepatic metabolic adaptation is crucial for sepsis management.

Purpose of the Study:

• To investigate the metabolic and energetic reprogramming of hepatocytes during sepsis.
• To identify key metabolic pathways and molecular changes in the liver following sepsis induction.
• To evaluate the therapeutic potential of targeting mitochondrial energy metabolism in sepsis.

Main Methods:

• Utilized a cecal ligation and puncture (CLP) mouse model to induce sepsis.
• Performed comprehensive metabolomic, lipidomic, and transcriptional profiling of liver tissue.
• Analyzed changes in the tricarboxylic acid (TCA) cycle, lipid metabolism, and redox balance.
• Assessed the effect of dichloroacetate (a PDK inhibitor) on hepatic metabolism.

Main Results:

• Sepsis significantly reprogrammed hepatocyte lipid metabolism, TCA cycle energetics, and redox balance.
• Observed increased TCA metabolites (citrate, cis-aconitate, itaconate) and triglyceride accumulation in septic hepatocytes.
• Transcriptional profiling confirmed and expanded upon observed metabolic changes.
• Dichloroacetate administration reversed sepsis-induced metabolic dysfunction and mitochondrial issues.

Conclusions:

• Sepsis induces significant hepatic metabolic dysfunction, affecting lipid metabolism and energy homeostasis.
• Targeting the mitochondrial pyruvate dehydrogenase kinase (PDK)/pyruvate dehydrogenase complex (PDC) pathway offers a potential therapeutic strategy.
• Restoring the PDC/PDK energy homeostat can rebalance metabolic and transcriptional changes in the liver during sepsis.