RXRα Suppression Drives Hepatic Metabolic and Immune Dysfunction in Sepsis​: Gene induction by BEX in Sham & CLP (8h)

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.