Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration

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BACKGROUND & AIMS: Constitutive androstane receptor transcriptionally regulates xenobiotic detoxification, metabolism, and hepatocyte proliferation. Although constitutive androstane receptor activation promotes regeneration and its loss impairs recovery after extreme hepatectomy (86%-90% liver resection), its temporal role during standard liver regeneration following two-thirds partial hepatectomy remains unclear. METHODS: We quantified DNA synthesis, gene expression, and bile acid concentrations and composition in Car knockout and wild-type mice across regenerative time points after partial hepatectomy. RESULTS: Car transcript expression is dynamically regulated during regeneration, peaking at 12 hours and plummeting below basal levels by 72 hours post-partial hepatectomy. Despite this, Car knockout livers regenerate comparably to wild-type livers. Notably, Car knockout mice display an exaggerated increase in hepatic and systemic bile acid levels after partial hepatectomy, revealing an unexpected metabolic role for constitutive androstane receptor. Pharmacologic reduction of bile acid levels with cholestyramine in Car knockout mice attenuated 5-bromo-2'-deoxyuridine 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: Constitutive androstane receptor exerts a temporally regulated metabolic role during liver regeneration. Car deletion amplifies the post-hepatectomy bile acid surge, which acts as a compensatory proproliferative signal to sustain regeneration.

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