Constitutive Androstane Receptor (CAR) regulates bile acid homeostasis and metabolism during liver regeneration

BACKGROUND & AIMS: Constitutive Androstane Receptor (CAR) transcriptionally regulates xenobiotic detoxification, metabolism, and hepatocyte proliferation. While CAR activation promotes regeneration and its loss impairs recovery after extreme hepatectomy (86-90% liver resection), its temporal role during standard liver regeneration following 2/3rd partial hepatectomy (PHx) remains unclear.

METHODS: We quantified DNA synthesis, gene expression, and bile acid (BA) concentrations and composition in Car knockout (CarKO) and wild-type (WT) mice across regenerative time points after PHx.

RESULTS: Car transcript expression is dynamically regulated during regeneration, peaking at 12 hours and plummeting below basal levels by 72 hours post-PHx. Despite this, CarKO livers regenerate comparably to WT livers. Notably, CarKO mice display an exaggerated increase in hepatic and systemic BA levels after PHx, revealing an unexpected metabolic role for CAR. Pharmacological reduction of BA levels with cholestyramine in CarKO mice attenuated BrdU incorporation and proliferation-associated gene expression. Analysis of single-cell RNA sequencing data further showed that Car and its target genes are enriched in hypermetabolic, rather than proliferating, hepatocyte population during regeneration.

CONCLUSIONS: CAR exerts a temporally regulated metabolic role during liver regeneration. Car deletion amplifies the post-hepatectomy BA surge, which acts as a compensatory pro-proliferative signal to sustain regeneration.