Farnesoid X receptor, hepatocyte nuclear factors 1α and 3β are essential for transcriptional activation of the liver-specific organic anion transporter-2 gene

Hideo Ohtsuka, Takaaki Abe, Tohru Onogawa, Noriko Kondo, Takeaki Sato, Hiroshi Oshio, Hiroya Mizutamari, Tsuyoshi Mikkaichi, Masaya Oikawa, Toshiki Rikiyama, Yu Katayose, Michiaki Unno

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Background: We isolated the human liver-specific organic anion transporter gene, LST-2 (OATP8/SLCO1B3), which is exclusively expressed in the basolateral membrane of the hepatocytes. In this study, we analyzed the transcriptional regulation of the LST-2 gene in hepatocyte-derived cells and the effect of bile acid. Methods: Transcriptional activity of the LST-2 gene was measured using a human LST-2 promoter-luciferase reporter plasmid under various concentrations of bile acids. Electrophoresis mobility shift assays of farnesoid X receptor (FXR), hepatocyte nuclear factor (HNF) 1α, and HNF3β were performed. Results: Luciferase analysis showed that the 5′-flanking region from -180 to -20bp is responsible for LST-2 transcriptional activity. By site-directed mutation analysis, it was revealed that the consensus binding sites for FXR, HNF1α, and HNF3β play important roles in the transcriptional activity of the LST-2 gene. By electrophoresis mobility shift assay, we observed specific protein-DNA complexes of FXR, HNF1α, and HNF-3β. Luciferase activity was increased fivefold when chenodeoxycholate or deoxycholate were added. Northern blot analyses revealed that the expression of LST-2 was increased by addition of chenodeoxycholate or deoxycholate in a dose-dependent manner. Conclusions: This study demonstrated that the transcription of the LST-2 gene is regulated by three transcription factors, FXR, HNF1α, and HNF3β. HNF1α and HNF3β might contribute to its liver-specific expression, and FXR might play a role in its transcriptional activation by bile acids.

Original languageEnglish
Pages (from-to)369-377
Number of pages9
JournalJournal of gastroenterology
Volume41
Issue number4
DOIs
Publication statusPublished - 2006 Apr 1

Keywords

  • Bile acid
  • Hep3B
  • Organic anion transporter
  • THLE-3
  • Transcription factor

ASJC Scopus subject areas

  • Gastroenterology

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