Work

Estradiol-induced disruption of CAR signaling leads to bile acid homeostasis dysregulation in a murine model of intrahepatic cholestasis of pregnancy and is reversed by CAR ligands

Year: 2026

Type: article

Abstract: Estrogens impair bile acid (BA) homeostasis, supporting the development of intrahepatic cholestasis of pregnancy (ICP). ICP is characterized by elevated serum BA levels, pruritus, and an increased risk of adverse perinatal outcomes. The constitutive androstane receptor (CAR) regulates genes involved in xenobiotic and BA detoxification. Previous studies suggest that CAR activation is protective in bile duct ligation–induced cholestasis and that the main genes involved in BA elimination are downregulated in ethinylestradiol (EE)-induced cholestasis in mice. Here, we examined whether CAR ligands could ameliorate cholestasis and prevent liver injury in an EE-induced cholestasis model using biochemical, transcriptomic, and BA metabolomic analyses. We demonstrate that estradiol significantly downregulates and inhibits CAR in the liver. Consistently, EE significantly suppresses the expression of hepatic CAR target genes. The murine CAR agonist TCPOBOP partially restores the expression of selected detoxification genes, improves plasma alkaline phosphatase activity, and decreases hepatic BA accumulation. In humanized PXR–CAR–CYP3A4/3A7 mice with EE-induced cholestasis, MI763F, a novel and potent human CAR agonist, recapitulates the effects of TCPOBOP on key genes involved in BA metabolism and the BA metabolome, and significantly reduces hepatic BA accumulation. These results demonstrate that CAR ligands counteract EE-mediated disruption of genes involved in BA homeostasis.

Source: Acta Pharmaceutica Sinica B

DOI: 10.1016/j.apsb.2026.08.027