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Activation of FXR by obeticholic acid induces hepatic gene expression of SR-BI through a novel mechanism of transcriptional synergy with the nuclear receptor LXR

  • Authors:
    • Bin Dong
    • Amar B. Singh
    • Grace L. Guo
    • Mark Young
    • Jingwen Liu
  • View Affiliations / Copyright

    Affiliations: Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA, Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA, Mistral Therapeutics, San Diego, CA 92121, USA
    Copyright: © Dong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1927-1938
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    Published online on: March 18, 2019
       https://doi.org/10.3892/ijmm.2019.4136
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Abstract

The farnesoid X receptor (FXR) is known to regulate the gene expression of SR‑BI, which mediates plasma high‑density lipoprotein (HDL)‑cholesterol uptake. Our previous study demonstrated that the activation of FXR by obeticholic acid (OCA) lowered plasma HDL‑cholesterol levels and increased the hepatic mRNA and protein expression levels of SR‑BI in hypercholesterolemic hamsters, but not in normolipidemic hamsters, suggesting that dietary cholesterol may be involved in the OCA‑induced transcription of SR‑BI. In the present study, a functional 90‑base‑pair regulatory region was identified in the first intron of the SR‑BI gene of hamster and mouse that contains a FXR response element (IR‑1) and an adjacent liver X receptor (LXR) response element (LXRE). By in vitro DNA binding and luciferase reporter gene assays, it was demonstrated that FXR and LXR bind to their recognition sequences within this intronic region and transactivate the SR‑BI reporter gene in a synergistic manner. It was also shown that mutations at either the IR‑1 site or the LXRE site eliminated OCA‑mediated gene transcription. Utilizing chow‑fed hamsters as an in vivo model, it was demonstrated that treating normolipidemic hamsters with OCA or GW3965 alone did not effectively induce levels of SR‑BI, whereas their combined treatment significantly increased the mRNA and protein levels of SR‑BI in the liver. The study further investigated effects of FXR and LXR coactivation on the gene expression of SR‑BI in human liver cells. The intronic FXRE and LXRE regulatory region was not conserved in the human SR‑BI genomic sequence, however, higher mRNA expression levels of SR‑BI were observed in human primary hepatocytes and HepG2 cells exposed to combined treatments of FXR and LXR agonists, compared with those in cells exposed to individual ligand treatment. Therefore, these results suggest that human SR‑BI gene transcription may also be subject to concerted activation by FXR and LXR, mediated via currently unidentified regulatory sequences.
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Copy and paste a formatted citation
Spandidos Publications style
Dong B, Singh AB, Guo GL, Young M and Liu J: Activation of FXR by obeticholic acid induces hepatic gene expression of SR-BI through a novel mechanism of transcriptional synergy with the nuclear receptor LXR. Int J Mol Med 43: 1927-1938, 2019.
APA
Dong, B., Singh, A.B., Guo, G.L., Young, M., & Liu, J. (2019). Activation of FXR by obeticholic acid induces hepatic gene expression of SR-BI through a novel mechanism of transcriptional synergy with the nuclear receptor LXR. International Journal of Molecular Medicine, 43, 1927-1938. https://doi.org/10.3892/ijmm.2019.4136
MLA
Dong, B., Singh, A. B., Guo, G. L., Young, M., Liu, J."Activation of FXR by obeticholic acid induces hepatic gene expression of SR-BI through a novel mechanism of transcriptional synergy with the nuclear receptor LXR". International Journal of Molecular Medicine 43.5 (2019): 1927-1938.
Chicago
Dong, B., Singh, A. B., Guo, G. L., Young, M., Liu, J."Activation of FXR by obeticholic acid induces hepatic gene expression of SR-BI through a novel mechanism of transcriptional synergy with the nuclear receptor LXR". International Journal of Molecular Medicine 43, no. 5 (2019): 1927-1938. https://doi.org/10.3892/ijmm.2019.4136
Copy and paste a formatted citation
x
Spandidos Publications style
Dong B, Singh AB, Guo GL, Young M and Liu J: Activation of FXR by obeticholic acid induces hepatic gene expression of SR-BI through a novel mechanism of transcriptional synergy with the nuclear receptor LXR. Int J Mol Med 43: 1927-1938, 2019.
APA
Dong, B., Singh, A.B., Guo, G.L., Young, M., & Liu, J. (2019). Activation of FXR by obeticholic acid induces hepatic gene expression of SR-BI through a novel mechanism of transcriptional synergy with the nuclear receptor LXR. International Journal of Molecular Medicine, 43, 1927-1938. https://doi.org/10.3892/ijmm.2019.4136
MLA
Dong, B., Singh, A. B., Guo, G. L., Young, M., Liu, J."Activation of FXR by obeticholic acid induces hepatic gene expression of SR-BI through a novel mechanism of transcriptional synergy with the nuclear receptor LXR". International Journal of Molecular Medicine 43.5 (2019): 1927-1938.
Chicago
Dong, B., Singh, A. B., Guo, G. L., Young, M., Liu, J."Activation of FXR by obeticholic acid induces hepatic gene expression of SR-BI through a novel mechanism of transcriptional synergy with the nuclear receptor LXR". International Journal of Molecular Medicine 43, no. 5 (2019): 1927-1938. https://doi.org/10.3892/ijmm.2019.4136
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