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

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.