LXR alpha transactivates mouse organic solute transporter alpha and beta via IR-1 elements shared with FXR

Autor: Saori Koh, Masae Okuwaki, Hiroshi Suzuki, Tappei Takada, Yuki Iwayanagi, Hiroshi Fujii, Yoshiaki Kariya
Rok vydání: 2006
Předmět:
Transcriptional Activation
DNA
Complementary
5' Flanking Region
Genetic Vectors
Molecular Sequence Data
Pharmaceutical Science
Receptors
Cytoplasmic and Nuclear
Electrophoretic Mobility Shift Assay
Biology
Retinoid X receptor
Intestinal absorption
Transactivation
Mice
Genes
Reporter
Transcriptional regulation
Animals
Pharmacology (medical)
Amino Acid Sequence
Cloning
Molecular
Liver X receptor
Luciferases
Transcription factor
Liver X Receptors
Repetitive Sequences
Nucleic Acid
Pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Organic Chemistry
Membrane Transport Proteins
Orphan Nuclear Receptors
Cell biology
DNA-Binding Proteins
Biochemistry
Hepatocyte nuclear factor 4
Hepatocyte Nuclear Factor 4
Mutation
Molecular Medicine
Farnesoid X receptor
Biotechnology
Transcription Factors
Zdroj: Pharmaceutical research. 24(2)
ISSN: 0724-8741
Popis: Recently identified organic solute transporter (Ost) alpha and beta 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 Ostalpha/beta promoter-luciferase reporter constructs. Co-transfection of the constructs with farnesoid X receptor (FXR) and retinoid X receptor alpha (RXRalpha) or liver X receptor alpha (LXRalpha) and RXRalpha into Caco-2 cells induced the transcriptional activities of both Ost alpha and beta and further increases were observed following treatment with each agonist. Sequence analyses indicated the presence of IR-1 regions in Ostalpha and Ostbeta promoters, which was confirmed by the finding that the deletion of IR-1 sequences abolished the response to FXR and LXRalpha. Furthermore, mutations in IR-1 reduced the FXR- and LXRalpha-dependent transactivation of Ostalpha/beta. Together with the detection of direct binding of FXR/RXRalpha and LXRalpha/RXRalpha to the IR-1 elements, the presence of functional FXRE/LXRE was revealed in the promoter region of both Ostalpha and Ostbeta. In addition, the stimulatory effect of FXR/RXRalpha and LXRalpha/RXRalpha on Ostalpha, but not on Ostbeta, was further enhanced by HNF-4alpha.It was concluded that LXRalpha/RXRalpha transcriptionally regulate mouse Ostalpha/beta via IR-1 elements shared with FXR/RXRalpha. Exposure to FXR/LXRalpha modulators may affect the disposition of Ostalpha/beta substrates.
Databáze: OpenAIRE
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