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

Content Provider	Springer Nature Link
Author	Okuwaki, Masae Takada, Tappei Iwayanagi, Yuki Koh, Saori Kariya, Yoshiaki Fujii, Hiroshi Suzuki, Hiroshi
Copyright Year	2006
Abstract	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.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.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.
Starting Page	390
Ending Page	398
Page Count	9
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	24
Issue Number	2
e-ISSN	1573904X
Language	English
Publisher	Springer US
Publisher Date	2006-12-20
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	bile acids drug transporter enterohepatic circulation intestinal transport transcriptional regulation Pharmacology/Toxicology Pharmacy Biochemistry Medical Law Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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