HNF4a contributes to hepatic CAR dysfunction in polymicrobial sepsis

Constitutive androstane receptor (CAR) is a xenobiotic nuclear receptor mainly expressed in the liver, where it regulates drug metabolism and energy homeostasis. CAR has emerged as a promising therapeutic target for diabetes, fatty liver disease, and alcoholic liver disease, but it has not been investigated in the context of sepsis. Here, we show that sepsis impairs CAR function in the liver, partly due to reduced transcription mediated by HNF4a, the key liver identity transcription factor, and partly due to decreased DNA binding, caused by chromatin remodelling, also mediated by HNF4a. This impairment leads to the downregulation of several genes involved in monocarboxylic acid, fatty acid, and xenobiotic metabolism, contributing to increased sepsis lethality, and is associated with an elevated hepatic acute phase response. NCT protects against sepsis by enhancing HNF4a binding to the CAR promoter, thereby increasing both CAR transcription and activity. Overall design: A total of four conditions were used: SHAM+CTRL, SHAM+TCPOBOP, CLP+CTRL and CLP+TCPOBOP, with 4 biological replicates each, for a total of 16 samples. Livers were isolated and processed for transcriptional profiling by RNA-seq