Effect And Molecular Mechanism Of Farnesoid X Receptor Agonist On Metabolism Of Bile Acid In Rats With Estrogen-Induced Intrahepatic Cholestasis Of Pregnancy

OBJECTIVE: To compare the effect and investigate the mechanism of potent farnesoid X receptor (FXR) ligand-chenodeoxycholic acid(CDCA) with ursodeoxycholic acid(UDCA) on metabolism of bile acid in rats with estrogen-induced intrahepatic cholestasis of pregnancy(ICP).METHOD: We set up ICP rat model with Estradiol Benzoate(EB,2.5 mg·kg^-1·d^-1). Then CDCA(100 mg·kg^-1 daily) or UDCA(50 mg·kg^-1 daily) was administrated to the model group for 5 days randomly. Serum aminotransferase (ALT,AST,ALP) and total bile acid (TBA) levels were analyzed before and after the administration of the drug. The pathologic changes of the maternal liver, the length of the fetal body and tail, its bodyweight, and the fatality after administration were recorded. The expression of FXR and BSEP in the liver of rats were examined by immunohistochemistry and reverse transcription PCR.RESULTS: Compared with control group, the model group rats showed high level of ALT,AST,ALP,TBA and fetal death(P<0.0083), the length of the fetal body and tail and its bodyweight showed no significant change. Pathohistological examination under microscope showed hepatocyte swelling, narrowed sinusoid and bile canaliculus dilated. The expression of mRNA and protein of FXR in maternal liver were much higher in model group (0.53±0.06 vs 0.40±0.04, P<0.05 and 1.83±0.05 vs 1.26±0.02, P<0.0083, respectively), but those of BSEP decreased significantly (0.76±0.07 vs 1.26±0.41, P<0.0083 and 1.46±0.06 vs 2.15±0.04, P<0.0083, respectively). Compared with model group, the level of ALT, AST and ALP in the UDCA group decreased dramatically(P<0.0083). The expression of FXR increased dramatically(P<0.0083). But the level of TBA, the length of the fetal body and tail, its bodyweight, the fatality and the expression of BSEP didn't improve. Pathohistological examination showed apparent fatty degeneration, and the formation of hepatic lobules was normal. In CDCA group, the level of TBA was much lower than in the model group(17.2±4.06 vs 29.3±6.37, P<0.0083). And the expression of FXR and BSEP rose dramatically(FXR:mRNA 0.76±0.09 vs 0.53±0.06, P<0.05, protein 2.35±0.06 vs 1.83±0.05, P<0.0083; BSEP: 0.99±0.21 vs 0.76±0.07, P<0.0083 and 1.88±0.03 vs 1.46±0.06, P<0.0083, respectively). But there is no difference in fetal death.CONCLUSIONS: Our studies showed that FXR plays an important role in the modulation of metabolism of acid bile. Estrogen might bring about intrehepatic cholestasis by inhibiting the function of FXR and then the expression of its target gene-BSEP. Treatment with UDCA appears to improve biochemical index, with the exception of the total bile acid and the fetal fatality. FXR agonists-CDCA may decrease the level of serum TBA effectively by upregulating the expression of FXR and BSEP and then transport of the bile acid.It might represent a new idea and traget for the treatment of ICP.