Speaker
Description
Background: Estrogens disrupt bile acid (BA) homeostasis and contribute to the development of intrahepatic cholestasis of pregnancy (ICP). ICP is associated with increased serum BA and bilirubin levels, pruritus, and a higher risk of adverse perinatal outcomes. The constitutive androstane receptor (CAR) plays a key role in regulating genes involved in xenobiotic metabolism and BA detoxification. Previous studies indicate that CAR activation exerts protective effects in bile duct ligation–induced cholestasis, while genes critical for BA elimination are suppressed in ethinylestradiol (EE)–induced cholestasis in mice.
Methods: We investigated whether CAR ligands can alleviate cholestasis and protect against liver injury in an EE-induced mouse model using biochemical, transcriptomic, and BA metabolomic analyses.
Results: Estradiol markedly suppresses hepatic CAR activity, leading to downregulation of CAR target genes. In EE-induced cholestasis, the murine CAR agonist TCPOBOP partially restores detoxification gene expression, improves plasma alkaline phosphatase activity, and reduces hepatic BA accumulation. In humanized PXR-CAR-CYP3A4/3A7 mice, the human CAR agonist MI763F mirrors these effects, normalizing bile acid–related gene expression and metabolome changes while significantly lowering hepatic BA levels.
Conclusions: Our results demonstrate that estradiol suppresses CAR activity, contributing to bile acid accumulation and cholestasis. Pharmacological CAR activation mitigates these effects, highlighting CAR as a promising therapeutic target for estrogen-driven cholestasis, including ICP.
Acknowledgments:
This research was funded by GAUK No. 117124 and NETPHARM, project ID CZ.02.01.01/00/22_008/0004607, is co-funded by EU.
