Protective role of hydroxysteroid sulfotransferase in lithocholic acid—in—duced liver toxicity

Supplement of 1% lithocholic acid (LCA) in the diet for 5-9d resulted in elevated levels of the marker for liver damage AST and ALP activities in both FXR-null and wild-type female mice.The levels were clearly higher in wild-type mice than in FXR-null mice,in spite of the diminished expression of a bile salt export pump(Bsep) in the latter.Consistent with liver toxicity marker activities,serum and liver levels of bile acide,particularly LCA and tauro LCA,were clearly higher in wild-type mice than in FXR-null mice after 1% LCA supplement.Marked increases in hepatic sulfating activity for LCA(5.5-fold) and hydroxysteroid sulfotransferase St2a(5.8-fold) were detected in liver of FXR-null mice.Liver St2a content was inversely correlated with levels of ALP.In contrast,microsomal LCA 6-hydroxylation was not increased and in fact lower in FXR-null mice compared in wild-type mice.Clear decreases in mRNA encoding Ntcp,Oatpl and Lst-1 transporters function in bild acid import were detected in LCA fed mice.These transporter levels are higher in FXR-null mice than in wild-type mice after 1% LCA supplement.No obvious changes were detected in the Mrp2,Mrp3 and Mrp4 mRNAs.These results indicate that hydroxysteroid sulfotransferase is reuired for protection against LCA-induced liver damage.