A critical role for Hepatocyte Nuclear Factor 4 alpha in polymicrobial sepsis-associated metabolic reprogramming and death: effect of CLP/SHAM in Hnf4a WT and KO mice

In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in expression of hepatic PPARa, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARa downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4a, which has strong impact on the expression of several important nuclear receptors, including PPARa. HNF4a depletion in hepatocytes dramatically increases sepsis lethality, steatosis and organ damage and prevents an adequate response towards IL6, which is critical for liver regeneration and survival. An HNF4a agonist protects against sepsis at all possible levels, irrespectively of bacterial loads, suggesting HNF4a is crucial in disease tolerance to sepsis. In conclusion, hepatic HNF4a fails in sepsis, causing PPARa downregulation and metabolic problems and a disturbed IL6-mediated acute phase response. The data open new insights and therapeutic options in sepsis. Overall design: RNA-seq in WT mice and Hnf4a KO (inducible: induced by tamoxifen) mice sebjected to SHAM or CLP surgery, livers were isolated for transcripome profiling, using 4 biological replicates