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A critical role for Hepatocyte Nuclear Factor 4 alpha in polymicrobial sepsis-associated metabolic reprogramming and death: HNF4A ChIP-seq in the CLP sepsis model (ChIP-Seq)

ABSTRACT: In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in 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 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 towards IL6, which is critical for liver regeneration and survival. An HNF4α agonist protects against sepsis at all possible levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in disease tolerance to sepsis. In conclusion, hepatic HNF4α fails in sepsis, causing PPARα downregulation and metabolic problems and a disturbed IL6-mediated acute phase response. The data open new insights and therapeutic options in sepsis.

ORGANISM(S): Mus musculus

PROVIDER: GSE245682 | GEO | 2023/10/31

REPOSITORIES: GEO

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A critical role for Hepatocyte Nuclear Factor 4 alpha in polymicrobial sepsis-associated metabolic reprogramming and death: ATAC-seq after CLP sepsis model

Project description:In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in 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 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 towards IL6, which is critical for liver regeneration and survival. An HNF4α agonist protects against sepsis at all possible levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in disease tolerance to sepsis. In conclusion, hepatic HNF4α fails in sepsis, causing PPARα downregulation and metabolic problems and a disturbed IL6-mediated acute phase response. The data open new insights and therapeutic options in sepsis.

2023-10-31 | GSE244821 | GEO

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

2024-03-12 | GSE260635 | GEO

A critical role for Hepatocyte Nuclear Factor 4 alpha in polymicrobial sepsis-associated metabolic reprogramming and death: effect of IL6 in Hnf4a WT and KO mice

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A critical role for Hepatocyte Nuclear Factor 4 alpha in polymicrobial sepsis-associated metabolic reprogramming and death: H3K27ac and H3K4me3 after CLP sepsis model

Project description: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 PPARα. Since PPARα 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 PPARα downregulation in sepsis is unknown. A potential mechanism resides in HNF4α, which regulates liver lipid metabolism directly by activating Ppara gene expression and indirectly by interacting with PPARα itself. A proper functioning of HNF4α is essential for maintaining liver identity. We here show that sepsis causes a progressive HNF4α loss-of-function in the liver, which impacts expression of several nuclear receptors, among which PPARα, and is characterized by a reduced HNF4α DNA binding. Specific HNF4α depletion in the liver dramatically worsens sepsis lethality, associated with increased steatosis and hepatocyte damage. HNF4α dysfunction also prevents an adequate response towards IL6, controlled by CEBPβ and STAT3, which is critical for a proper liver regeneration and survival. In addition, the HNF4α agonist NCT partially protects against sepsis by limiting hepatic steatosis and liver dysfunction. In conclusion, hepatic HNF4α fails in sepsis, causing PPARα 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

2024-03-12 | GSE260577 | GEO

Hepatic PPARα function and lipid metabolic pathways are dysregulated in polymicrobial sepsis

Project description:<p>Despite intensive research and constant medical progress, sepsis remains one of the most urgent unmet medical needs of today. Most studies have been focused on the inflammatory component of the disease, however, recent advances support the notion that sepsis is accompanied by extensive metabolic perturbations. During times of limited caloric intake and high energy needs, the liver acts as the central metabolic hub in which PPARα is crucial to coordinate the breakdown of fatty acids. The role of hepatic PPARα in liver dysfunction during sepsis has hardly been explored. We demonstrate that sepsis leads to a starvation response that is hindered by the rapid decline of hepatic PPARα levels, causing excess free fatty acids, leading to lipotoxicity, and glycerol. In addition, treatment of mice with the PPARα agonist pemafibrate protects against bacterial sepsis by improving hepatic PPARα function, reducing lipotoxicity and tissue damage. Since lipolysis is also increased in sepsis patients and pemafibrate protects after the onset of sepsis, these findings may point towards new therapeutic leads in sepsis. </p>

2020-01-10 | MTBLS1386 | MetaboLights

Hepatic PPARα dysfunction in porcine sepsis

Project description:Hepatic PPARα dysfunction in porcine sepsis

| PRJNA904738 | ENA

Hepatic PPARα function and lipid metabolic pathways are dysregulated in polymicrobial sepsis

Project description:Despite intensive research and constant medical progress, sepsis remains one of the most urgent unmet medical needs of today. Most studies have been focused on the inflammatory component of the disease, however, recent advances support the notion that sepsis is accompanied by extensive metabolic perturbations. During times of limited caloric intake and high energy needs, the liver acts as the central metabolic hub in which PPARa is crucial to coordinate the breakdown of fatty acids. The role of hepatic PPARa in liver dysfunction during sepsis has hardly been explored. We demonstrate that sepsis leads to a starvation response that is hindered by the rapid decline of hepatic PPARa levels, causing excess free fatty acids, leading to lipotoxicity, and glycerol. In addition, treatment of mice with the PPARa agonist pemafibrate protects against bacterial sepsis by improving hepatic PPARa function, reducing lipotoxicity and tissue damage. Since lipolysis is also increased in sepsis patients and pemafibrate protects after the onset of sepsis, these findings may point towards new therapeutic leads in sepsis.

2019-11-23 | GSE139484 | GEO

Hepatic PPARα function and lipid metabolic pathways are dysregulated in polymicrobial sepsis

Project description:Hepatic PPARα function and lipid metabolic pathways are dysregulated in polymicrobial sepsis

| PRJNA579938 | ENA

Hepatic PPARα dysfunction in porcine sepsis

Project description: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 PPARα in liver dysfunction during sepsis has recently been described, and restoring PPARα 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 PPARα signaling in the livers of septic pigs and reduced PPARα levels correlated well with disease severity. As PPARα 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 PPARα signaling in the clinic.

2022-11-28 | GSE218636 | GEO

Polymicrobial sepsis-induced Myocardial Depression Transcriptional Profile

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