A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death

In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in the expression of hepatic PPAR alpha, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPAR alpha downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4 alpha, which has a strong impact on the expression of several important nuclear receptors, including PPAR alpha. HNF4 alpha depletion in hepatocytes dramatically increases sepsis lethality, steatosis, and organ damage and prevents an adequate response to IL6, which is critical for liver regeneration and survival. An HNF4 alpha agonist protects against sepsis at all levels, irrespectively of bacterial loads, suggesting HNF4 alpha is crucial in tolerance to sepsis. In conclusion, hepatic HNF4 alpha activity is decreased during sepsis, causing PPAR alpha downregulation, metabolic problems, and a disturbed IL6-mediated acute phase response. The findings provide new insights and therapeutic options in sepsis. Besides inflammation, metabolic dysregulation also contributes to sepsis lethality, offering therapeutic potential. This study shows that loss of hepatic HNF4 alpha activity in sepsis disrupts PPAR alpha-regulated lipid metabolism and the acute phase response, both of which can be restored by the agonist NCT.Hepatic HNF4 alpha loses its function during sepsis due to alterations in its chromatin binding.These changes in HNF4 alpha chromatin binding during sepsis mainly affect H3K27 acetylation, thereby modulating enhancer activity, with little effect on chromatin accessibility.Hepatocyte-specific HNF4 alpha knockout mice show reduced PPAR alpha expression and activity, decreased IL6-induced acute phase response, and increased lipid accumulation during sepsis, all of these contributing to sepsis lethality.The HNF4 alpha agonist NCT protects against sepsis by preventing lipid metabolic dysregulation caused by HNF4 alpha ...