Chenodeoxycholic acid-mediated activation of the farnesoid X receptor negatively regulates hydroxysteroid sulfotransferase.
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.
Miyata
Masaaki
M
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Sendai, Japan. miyata@mail.pharm.tohoku.ac.jp
Matsuda
Yoshiki
Y
Tsuchiya
Hiroyuki
H
Kitada
Hirotaka
H
Akase
Takanori
T
Shimada
Miki
M
Nagata
Kiyoshi
K
Gonzalez
Frank J
FJ
Yamazoe
Yasushi
Y
D000818:Animals; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000378:metabolism / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000172:deficiency / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008095:Lithocholic Acid / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015238:Sulfotransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000819:agonists* / Q000172:deficiency / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D008095:Lithocholic Acid; D011285:Pregnenolone Carbonitrile; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D015238:Sulfotransferases; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C099713:nuclear receptor subfamily 0, group B, member 2; C028152:alcohol sulfotransferase