TY - JOUR TI - Dichloroacetate reverses sepsis-induced hepatic metabolic dysfunction AU - Mainali, Rabina AU - Zabalawi, Manal AU - Long, David AU - Buechler, Nancy AU - Quillen, Ellen AU - Key, Chia-Chi AU - Zhu, Xuewei AU - Parks, John S AU - Furdui, Cristina AU - Stacpoole, Peter W AU - Martinez, Jennifer AU - McCall, Charles E AU - Quinn, Matthew A A2 - Molnár, Zsolt A2 - van der Meer, Jos WM A2 - Bauer, Michael A2 - Wang, Andrew VL - 10 PY - 2021 DA - 2021/02/22 SP - e64611 C1 - eLife 2021;10:e64611 DO - 10.7554/eLife.64611 UR - https://doi.org/10.7554/eLife.64611 AB - 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. KW - sepsis KW - liver KW - inflammation KW - metabolism KW - steatosis JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -