A critical role for Hepatocyte Nuclear Factor 4 alpha in polymicrobial sepsis-associated metabolic reprogramming and death: H3K27ac and H3K4me3 after CLP sepsis model
Sepsis is a maladaptive host response towards an infection leading to tissue damage, organ failure, and ultimately death. In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is hindered by hepatic disappearance of the key transcription factor PPARa. Since PPARa acts as a central player in intracellular catabolism of fatty acids (FAs), sepsis results in excess free FAs, which cause lipotoxicity. The mechanism upstream of the PPARa downregulation in sepsis is unknown. A potential mechanism resides in HNF4a, which regulates liver lipid metabolism directly by activating Ppara gene expression and indirectly by interacting with PPARa itself. A proper functioning of HNF4a is essential for maintaining liver identity. We here show that sepsis causes a progressive HNF4a loss-of-function in the liver, which impacts expression of several nuclear receptors, among which PPARa, and is characterized by a reduced HNF4a DNA binding. Specific HNF4a depletion in the liver dramatically worsens sepsis lethality, associated with increased steatosis and hepatocyte damage. HNF4a dysfunction also prevents an adequate response towards IL6, controlled by CEBPß and STAT3, which is critical for a proper liver regeneration and survival. In addition, the HNF4a agonist NCT partially protects against sepsis by limiting hepatic steatosis and liver dysfunction. In conclusion, hepatic HNF4a fails in sepsis, causing PPARa downregulation and consequent metabolic problems on the one hand, and a disturbed IL6-mediated acute phase response and regeneration on the other hand. The data open new insights and therapeutic options in sepsis Overall design: Chip-seq for histone modifications H3K27ac and H3K4me3 after in Sham and CLP conditions using 4biological replicates per group.