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LXR Alpha Transactivates Mouse Organic Solute Transporter Alpha and Beta via IR-1 Elements Shared with FXR

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Abstract

Purpose

Recently identified organic solute transporter (Ost) α and β are located on the basolateral membrane of enterocytes and may be responsible for the intestinal absorption of many substrates including bile acids. In the present study, the mechanism governing the transcriptional regulation of their expression was investigated.

Methods and Results

To clarify the transcriptional regulation of Osts, reporter gene assays were performed using mouse Ostα/β promoter-luciferase reporter constructs. Co-transfection of the constructs with farnesoid X receptor (FXR) and retinoid X receptor α (RXRα) or liver X receptor α (LXRα) and RXRα into Caco-2 cells induced the transcriptional activities of both Ost α and β and further increases were observed following treatment with each agonist. Sequence analyses indicated the presence of IR-1 regions in Ostα and Ostβ promoters, which was confirmed by the finding that the deletion of IR-1 sequences abolished the response to FXR and LXRα. Furthermore, mutations in IR-1 reduced the FXR- and LXRα-dependent transactivation of Ostα/β. Together with the detection of direct binding of FXR/RXRα and LXRα/RXRα to the IR-1 elements, the presence of functional FXRE/LXRE was revealed in the promoter region of both Ostα and Ostβ. In addition, the stimulatory effect of FXR/RXRα and LXRα/RXRα on Ostα, but not on Ostβ, was further enhanced by HNF-4α.

Conclusions

It was concluded that LXRα/RXRα transcriptionally regulate mouse Ostα/β via IR-1 elements shared with FXR/RXRα. Exposure to FXR/LXRα modulators may affect the disposition of Ostα/β substrates.

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Abbreviations

ASBT:

apical sodium-dependent bile acid transporter

BSEP:

bile salt export pump

CDCA:

chenodeoxycholic acid

EMSA:

electrophoretic mobility shift assay

FXR:

farnesoid X receptor

FXRE:

FXR/RXR binding element

HNF-4:

hepatocyte nuclear factor-4

I–BABP:

ileal–bile acid binding protein

IR-1:

inverted repeat-1

LXR:

liver X receptor

LXRE:

LXR/RXR binding element

OST:

organic solute transporter

RXR:

retinoid X receptor

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Acknowledgment

This work was supported by grants from The Japanese Ministry of Education, Science, Sports and Culture.

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Authors and Affiliations

  1. Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Masae Okuwaki, Tappei Takada, Yuki Iwayanagi, Saori Koh,  Yoshiaki Kariya & Hiroshi Suzuki

  2. Division of Molecular and Cellular Biology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8520, Japan

    Hiroshi Fujii

Authors
  1. Masae Okuwaki
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  2. Tappei Takada
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  3. Yuki Iwayanagi
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  4. Saori Koh
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  5. Yoshiaki Kariya
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  6. Hiroshi Fujii
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  7. Hiroshi Suzuki
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Corresponding author

Correspondence to Tappei Takada.

Additional information

M. Okuwaki and T. Takada contributed equally to this work.

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Okuwaki, M., Takada, T., Iwayanagi, Y. et al. LXR Alpha Transactivates Mouse Organic Solute Transporter Alpha and Beta via IR-1 Elements Shared with FXR. Pharm Res 24, 390–398 (2007). https://doi.org/10.1007/s11095-006-9163-6

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  • DOI: https://doi.org/10.1007/s11095-006-9163-6

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