Hnf4a Dysfunction in Sepsis: Gene induction by candiate ligand compound MJ041 in WT and KO primary hepatocytes
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE334989 | GEO | 2026/07/15
REPOSITORIES: GEO
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Project description:Sepsis is a life-threatening condition where a dysregulated host response to infection causes organ dysfunction and the collapse of metabolic and immune functions. Here, we identify hepatocyte Retinoid X Receptor α (RXRα) as a central integrator of host resilience during polymicrobial sepsis. We show that hepatic Rxra expression is transcriptionally dependent on the upstream regulator Hepatocyte Nuclear Factor 4 α (HNF4α), and that sepsis rapidly suppresses RXRα abundance at both the mRNA and protein levels. Transcriptomic profiling further reveals that the septic liver develops partial resistance to pharmacological RXR activation by its agonist Bexarotene (Bex). Despite this, prophylactic treatment with Bex preserves metabolic stability, enhances bacterial clearance, and improves survival. Using hepatocyte-specific inducible RXRα-deficient mice (RXRαiAlbKO), we demonstrate that this protective effect is strictly dependent on hepatocyte RXRα. Mechanistically, the loss of RXRα in hepatocytes leads to a profound reduction in the liver-resident macrophage, Kupffer cells (KC), resulting in uncontrolled bacterial dissemination and increased mortality. This defect is phenocopied by selective KC depletion. These findings establish that hepatocyte RXRα is essential for maintaining the hepatic macrophage niche, thereby linking hepatocellular transcriptional competence to systemic antibacterial defense.
2026-05-04 | GSE319852 | GEO
Project description:Sepsis is a life-threatening condition where a dysregulated host response to infection causes organ dysfunction and the collapse of metabolic and immune functions. Here, we identify hepatocyte Retinoid X Receptor α (RXRα) as a central integrator of host resilience during polymicrobial sepsis. We show that hepatic Rxra expression is transcriptionally dependent on the upstream regulator Hepatocyte Nuclear Factor 4 α (HNF4α), and that sepsis rapidly suppresses RXRα abundance at both the mRNA and protein levels. Transcriptomic profiling further reveals that the septic liver develops partial resistance to pharmacological RXR activation by its agonist Bexarotene (Bex). Despite this, prophylactic treatment with Bex preserves metabolic stability, enhances bacterial clearance, and improves survival. Using hepatocyte-specific inducible RXRα-deficient mice (RXRαiAlbKO), we demonstrate that this protective effect is strictly dependent on hepatocyte RXRα. Mechanistically, the loss of RXRα in hepatocytes leads to a profound reduction in the liver-resident macrophage, Kupffer cells (KC), resulting in uncontrolled bacterial dissemination and increased mortality. This defect is phenocopied by selective KC depletion. These findings establish that hepatocyte RXRα is essential for maintaining the hepatic macrophage niche, thereby linking hepatocellular transcriptional competence to systemic antibacterial defense.
2026-05-04 | GSE319754 | GEO
Project description:Sepsis is a life-threatening condition where a dysregulated host response to infection causes organ dysfunction and the collapse of metabolic and immune functions. Here, we identify hepatocyte Retinoid X Receptor α (RXRα) as a central integrator of host resilience during polymicrobial sepsis. We show that hepatic Rxra expression is transcriptionally dependent on the upstream regulator Hepatocyte Nuclear Factor 4 α (HNF4α), and that sepsis rapidly suppresses RXRα abundance at both the mRNA and protein levels. Transcriptomic profiling further reveals that the septic liver develops partial resistance to pharmacological RXR activation by its agonist Bexarotene (Bex). Despite this, prophylactic treatment with Bex preserves metabolic stability, enhances bacterial clearance, and improves survival. Using hepatocyte-specific inducible RXRα-deficient mice (RXRαiAlbKO), we demonstrate that this protective effect is strictly dependent on hepatocyte RXRα. Mechanistically, the loss of RXRα in hepatocytes leads to a profound reduction in the liver-resident macrophage, Kupffer cells (KC), resulting in uncontrolled bacterial dissemination and increased mortality. This defect is phenocopied by selective KC depletion. These findings establish that hepatocyte RXRα is essential for maintaining the hepatic macrophage niche, thereby linking hepatocellular transcriptional competence to systemic antibacterial defense.
2026-07-16 | GSE334778 | GEO
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.
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Project description:Background: Sepsis involves aberrant immune responses to infection, but the exact nature of this immune dysfunction remains poorly defined. Bacterial endotoxins like lipopolysaccharide (LPS) are potent inducers of inflammation, which has been associated with the pathophysiology of sepsis, but repeated exposure can also induce a suppressive effect known as endotoxin tolerance or cellular reprogramming. It has been proposed that endotoxin tolerance might be associated with the immunosuppressive state that was primarily observed during late-stage sepsis. However, this relationship remains poorly characterised. Here we clarify the underlying mechanisms and timing of immune dysfunction in sepsis. Methods: We defined a gene expression signature characteristic of endotoxin tolerance. Gene-set test approaches were used to correlate this signature with early sepsis, both newly and retrospectively analysing microarrays from 593 patients in 11 cohorts. Then we recruited a unique cohort of possible sepsis patients at first clinical presentation in an independent blinded controlled observational study to determine whether this signature was associated with the development of confirmed sepsis and organ dysfunction. Findings: All sepsis patients presented an expression profile strongly associated with the endotoxin tolerance signature (p < 0.01; AUC 96.1%). Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction. Interpretation: Our data support an updated model of sepsis pathogenesis in which endotoxin tolerance-mediated immune dysfunction (cellular reprogramming) is present throughout the clinical course of disease and related to disease severity. Thus endotoxin tolerance might offer new insights guiding the development of new therapies and diagnostics for early sepsis. For the RNA-Seq study reported here, 73 patients were recruited with deferred consent at the time of first examination in an emergency ward based on the opinion of physicians that there was a potential for the patient's condition to develop into sepsis. These were retrospectively divided into groups based on clinical features and compared to 11 non-urgent surgical controls.
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2021-08-23 | GSE182522 | GEO
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2023-12-31 | GSE250039 | GEO
Project description:Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication of sepsis characterized by acute and reversible myocardial dysfunction, for which effective targeted therapies remain limited. Artesunate (ART), a well-established first-line antimalarial agent, has attracted increasing attention for its anti-inflammatory, antioxidant, and cytoprotective properties. However, its role in SICM has not been fully elucidated. In this study, a murine SICM model was established using lipopolysaccharide to evaluate the effects of ART on animal mortality, cardiac function, histopathology, and biomarkers of myocardial injury.
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