Hepatic PPARa dysfunction in porcine sepsis

Despite decades of research, sepsis remains one of the most urgent unmet medical needs. Clinical trials in sepsis have mainly focused on targeting the inflammatory pathway, however, recent data indicate that sepsis should also be seen as a metabolic disease. Targeting metabolic dysregulations that take place in sepsis might uncover novel therapeutic opportunities to treat human sepsis patients. The role of PPARa in liver dysfunction during sepsis has recently been described, and restoring PPARa signaling proves to be successful in murine sepsis. To find out whether this therapy might also be helpful in human sepsis patients, we analyzed metabolic perturbations in liver of a porcine fecal peritonitis model. Resuscitation with fluids, antimicrobial therapy and abdominal drainage were applied to the pigs in order to mimic human clinical care. By using RNA-seq, we detected problems with PPARa signaling in the livers of septic pigs and reduced PPARa levels correlated well with disease severity. As PPARa regulates the expression of many genes involved in FA oxidation, reduced expression of these target genes concomitant with increased FFAs in plasma and ectopic lipid deposition in the liver was observed. The results obtained in pigs are in agreement with earlier observations in mice and support the potential of targeting defective PPARa signaling in the clinic. Overall design: Comparative gene expression profiling between livers from sham (3 biological replicates) and sepsis (9 biological replicates) pigs. Samples were taken between 14 and 18 hours after initiating the model for RNA-seq