Hepatoprotective Effect of S-ademetionine in the treatment of Intrahepatic Cholestasis through Farnesoid X Receptor Mechanism in Rats

Abstract

S-ademetionine (AdoMet) had been extensively studied in several clinical studies to treat Intrahepatic Cholestasis (IHC). The exact mechanism of action of AdoMet to regulator bile acid is unknown. Farnesoid X Receptor (FXR), a multifunctional nuclear receptor, plays vital roles in metabolism of bile acid. This study aims to investigate the mechanism of action of S-ademetionine in FXR to treat IHC. The IHC Sprague Dawley (SD) rat model was developed by administering Alpha Naphthyl Isothiocyanate (ANIT, 50 mg/kg). FXR excitant GW4064 (3 mg/kg) was used as a control to observe the impact of AdoMet (60 mg/kg) on the changes in serum direct levels in these rats. The hepatic histology between the HE staining contrast groups was performed using the Q-PCR to test FXR and the in situ hybridization was used to test the changes of bile salt export pump (Bsep), multidrug resistance-associated protein 2 (Mrp2), and Na+-taurocholate cotransporting polypeptide (Ntcp). AdoMet significantly reduced the serum direct levels and the hepatic tissue damage. AdoMet can also increase the expression of FXR, Bsep, Mrp2 and Ntcp. These findings confirm that AdoMet could reduce serum direct levels as well as improving hepatic tissue damage by enhancing the expression of FXR, Bsep, Mrp2 and Ntcp. These findings could also explain the great therapeutically effect of AdoMet in intrahepatic cholestasis.