Protective role of hydroxysteroid sulfotransferase in lithocholic acid-induced liver toxicity

Hirotaka Kitada, Masaaki Miyata, Toshifumi Nakamura, Aki Tozawa, Wataru Honma, Miki Shimada, Kiyoshi Nagata, Christopher J. Sinal, Grace L. Guo, Frank J. Gonzalez, Yasushi Yamazoe

    Research output: Contribution to journalArticlepeer-review

    119 Citations (Scopus)

    Abstract

    Supplement of 1% lithocholic acid (LCA) in the diet for 5-9 days resulted in elevated levels of the marker for liver damage aspartate aminotransferase and alkaline phosphatase activities in both farnesoid X receptor (FXR)-null and wild-type female mice. The levels were clearly higher in wild-type mice than in FXR-null mice, despite the diminished expression of a bile salt export pump in the latter. Consistent with liver toxicity marker activities, serum and liver levels of bile acids, particularly LCA and taurolithocholic acid, 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 (St) 2a (5.8-fold) were detected in liver of FXR-null mice. A 7.4-fold higher 3α-sulfated bile acid concentration was observed in bile of FXR-null mice fed an LCA diet compared with that of wild-type mice. Liver St2a content was inversely correlated with levels of alkaline phosphatase. In contrast, microsomal LCA 6β-hydroxylation was not increased and was in fact lower in FXR. null mice compared in wild-type mice. Clear decreases in mRNA encoding sodium taurocholate cotransporting polypeptide, organic anion transporting polypeptide 1, and liver-specific organic anion transporter-1 function in bile acid import were detected in LCA-fed mice. These transporter levels are higher in FXR-null mice than wild-type mice after 1% LCA supplement. No obvious changes were detected in the Mrp2, Mrp3, and Mrp4 mRNAs. These results indicate hydroxysteroid sulfotransferase-mediated LCA sulfation as a major pathway for protection against LCA-induced liver damage. Fur. thermore, Northern blot analysis using FXR-null, pregnane X receptor-null, and FXR-pregnane X receptor double-null mice suggests a repressive role of these nuclear receptors on basal St2a expression.

    Original languageEnglish
    Pages (from-to)17838-17844
    Number of pages7
    JournalJournal of Biological Chemistry
    Volume278
    Issue number20
    DOIs
    Publication statusPublished - 2003 May 16

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

    Fingerprint Dive into the research topics of 'Protective role of hydroxysteroid sulfotransferase in lithocholic acid-induced liver toxicity'. Together they form a unique fingerprint.

    Cite this