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 PPARα, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARα downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4α, which has a strong impact on the expression of several important nuclear receptors, including PPARα. HNF4α 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 HNF4α agonist protects against sepsis at all levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in tolerance to sepsis. In conclusion, hepatic HNF4α activity is decreased during sepsis, causing PPARα downregulation, metabolic problems, and a disturbed IL6-mediated acute phase response. The findings provide new insights and therapeutic options in sepsis.
Synopsis
Besides inflammation, metabolic dysregulation also contributes to sepsis lethality, offering therapeutic potential. This study shows that loss of hepatic HNF4α activity in sepsis disrupts PPARα-regulated lipid metabolism and the acute phase response, both of which can be restored by the agonist NCT.
Hepatic HNF4α loses its function during sepsis due to alterations in its chromatin binding.
These changes in HNF4α chromatin binding during sepsis mainly affect H3K27 acetylation, thereby modulating enhancer activity, with little effect on chromatin accessibility.
Hepatocyte-specific HNF4α knockout mice show reduced PPARα expression and activity, decreased IL6-induced acute phase response, and increased lipid accumulation during sepsis, all of these contributing to sepsis lethality.
The HNF4α agonist NCT protects against sepsis by preventing lipid metabolic dysregulation caused by HNF4α and PPARα loss-of-function and enhancing the hepatic acute phase response.
The HNF4α loss-of-function in sepsis could be translated to pigs and a humanized liver mouse model, emphasizing the relevance of the findings.
Besides inflammation, metabolic dysregulation also contributes to sepsis lethality, offering therapeutic potential. This study shows that loss of hepatic HNF4α activity in sepsis disrupts PPARα-regulated lipid metabolism and the acute phase response, both of which can be restored by the agonist NCT.