Chenodeoxycholic acid-mediated activation of the farnesoid X receptor negatively regulates hydroxysteroid sulfotransferase.

Masaaki Miyata, Yoshiki Matsuda, Hiroyuki Tsuchiya, Hirotaka Kitada, Takanori Akase, Miki Shimada, Kiyoshi Nagata, Frank J. Gonzalez, Yasushi Yamazoe

    Research output: Contribution to journalArticlepeer-review

    29 Citations (Scopus)

    Abstract

    Hydroxysteroid sulfotransferase catalyzing bile acid sulfation plays an essential role in protection against lithocholic acid (LCA)-induced liver toxicity. Hepatic levels of Sult2a is up to 8-fold higher in farnesoid X receptor-null mice than in the wild-type mice. Thus, the influence of FXR ligand (chenodeoxycholic acid (CDCA) and LCA) feeding on hepatic Sult2a expression was examined in FXR-null and wild-type mice. Hepatic Sult2a protein content was elevated in FXR-null and wild-type mice fed a LCA (1% and 0.5%) diet. Treatment with 0.5% CDCA diet decreased hepatic Sult2a to 20% of the control in wild-type mice, but increased the content in FXR-null mice. Liver Sult2a1 (St2a4) mRNA levels were reduced to 26% in wild-type mice after feeding of a CDCA diet, while no decrease was observed on Sult2a1 mRNA levels in FXR-null mice after CDCA feeding. A significant inverse relationship (r(2)=0.523) was found between hepatic Sult2a protein content and small heterodimer partner (SHP) mRNA level. PCN-mediated increase in Sult2a protein levels were attenuated by CDCA feeding in wild-type mice, but not in FXR-null mice. Human SULT2A1 protein and mRNA levels were decreased in HepG2 cells treated with the FXR agonists, CDCA or GW4064 in dose-dependent manners, although SHP mRNA levels were increased. These results suggest that SULT2A is negatively regulated through CDCA-mediated FXR activation in mice and humans.

    Original languageEnglish
    Pages (from-to)315-323
    Number of pages9
    JournalDrug metabolism and pharmacokinetics
    Volume21
    Issue number4
    DOIs
    Publication statusPublished - 2006 Aug

    ASJC Scopus subject areas

    • Pharmacology
    • Pharmaceutical Science
    • Pharmacology (medical)

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