Semi-quantitative profiling of bile acids in serum and liver reveals the dosage-related effects of dexamethasone on bile acid metabolism in mice

Abstract

Nuclear receptors, such as the pregnane X receptor (PXR) and glucocorticoid receptor (GR), play an important role in regulating the homeostasis of bile acids (BAs). In previous studies, two-week treatment of 1 mg/kg of dexamethasone (DEX) was used to activate GR in mice, whereas 4-day treatment of 75 mg/kg of DEX was chosen to activate PXR. However, little is known about the effect of DEX on circulating and hepatic BA profiles. In the present study, we reported a simple and rapid LC-MS method for semi-quantitative profiling of 39 BA species in mouse serum and liver. This method was applied to investigate the BA profiles in mice treated with either 1 mg/kg DEX for two weeks or 75 mg/kg DEX for 4 days. The gene expression, microsomal induction and liver enlargement in mice confirmed that PXR was activated by 4-day treatment of 75 mg/kg DEX, but not by two-week treatment of 1 mg/kg DEX. Two-week treatment of 1 mg/kg DEX markedly increased the circulating BAs, in particular conjugated primary BAs, suggesting a pro-cholestatic effect of DEX at low doses. In contrast, 4-day treatment of 75 mg/kg DEX increased BA hydroxylation and decreased hepatic BAs, in particular unconjugated secondary BAs, suggesting a BA-lowering and bacteria-suppressive effect of DEX at high doses. To conclude, a semi-quantitative LC-MS method was developed and applied to elucidate the dosage-related effects of DEX on serum and hepatic BA profiles in mice.