PXR Suppresses PPARα-Dependent HMGCS2 Gene Transcription by Inhibiting the Interaction between PPARα and PGC1α

Shizu, Ryota; Ezaki, Kanako; Sato, Takumi; Sugawara, Ayaka; Hosaka, Takuomi; Sasaki, Takamitsu; Yoshinari, Kouichi

doi:10.3390/cells10123550

Open AccessArticle

PXR Suppresses PPARα-Dependent HMGCS2 Gene Transcription by Inhibiting the Interaction between PPARα and PGC1α

by

Ryota Shizu

,

Kanako Ezaki

,

Takumi Sato

,

Ayaka Sugawara

,

Takuomi Hosaka

,

Takamitsu Sasaki

and

Kouichi Yoshinari

^*

Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan

^*

Author to whom correspondence should be addressed.

Cells 2021, 10(12), 3550; https://doi.org/10.3390/cells10123550

Submission received: 5 November 2021 / Revised: 3 December 2021 / Accepted: 13 December 2021 / Published: 16 December 2021

(This article belongs to the Collection Current Trends in Xenobiotic Sensing Nuclear Receptor Research—The Many Facets of PXR and CAR)

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Abstract

Background: PXR is a xenobiotic-responsive nuclear receptor that controls the expression of drug-metabolizing enzymes. Drug-induced activation of PXR sometimes causes drug–drug interactions due to the induced metabolism of co-administered drugs. Our group recently reported a possible drug–drug interaction mechanism via an interaction between the nuclear receptors CAR and PPARα. As CAR and PXR are structurally and functionally related receptors, we investigated possible crosstalk between PXR and PPARα. Methods: Human hepatocyte-like HepaRG cells were treated with various PXR ligands, and mRNA levels were determined by quantitative reverse transcription PCR. Reporter assays using the HMGCS2 promoter containing a PPARα-binding motif and mammalian two-hybrid assays were performed in HepG2 or COS-1 cells. Results: Treatment with PXR activators reduced the mRNA levels of PPARα target genes in HepaRG cells. In reporter assays, PXR suppressed PPARα-dependent gene expression in HepG2 cells. In COS-1 cells, co-expression of PGC1α, a common coactivator of PPARα and PXR, enhanced PPARα-dependent gene transcription, which was clearly suppressed by PXR. Consistently, in mammalian two-hybrid assays, the interaction between PGC1α and PPARα was attenuated by ligand-activated PXR. Conclusion: The present results suggest that ligand-activated PXR suppresses PPARα-dependent gene expression by inhibiting PGC1α recruitment.

Keywords: PXR; PPARα; PGC1α; nuclear receptor; coactivator; gene transcription; drug–drug interaction; liver function

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MDPI and ACS Style

Shizu, R.; Ezaki, K.; Sato, T.; Sugawara, A.; Hosaka, T.; Sasaki, T.; Yoshinari, K. PXR Suppresses PPARα-Dependent HMGCS2 Gene Transcription by Inhibiting the Interaction between PPARα and PGC1α. Cells 2021, 10, 3550. https://doi.org/10.3390/cells10123550

AMA Style

Shizu R, Ezaki K, Sato T, Sugawara A, Hosaka T, Sasaki T, Yoshinari K. PXR Suppresses PPARα-Dependent HMGCS2 Gene Transcription by Inhibiting the Interaction between PPARα and PGC1α. Cells. 2021; 10(12):3550. https://doi.org/10.3390/cells10123550

Chicago/Turabian Style

Shizu, Ryota, Kanako Ezaki, Takumi Sato, Ayaka Sugawara, Takuomi Hosaka, Takamitsu Sasaki, and Kouichi Yoshinari. 2021. "PXR Suppresses PPARα-Dependent HMGCS2 Gene Transcription by Inhibiting the Interaction between PPARα and PGC1α" Cells 10, no. 12: 3550. https://doi.org/10.3390/cells10123550

APA Style

Shizu, R., Ezaki, K., Sato, T., Sugawara, A., Hosaka, T., Sasaki, T., & Yoshinari, K. (2021). PXR Suppresses PPARα-Dependent HMGCS2 Gene Transcription by Inhibiting the Interaction between PPARα and PGC1α. Cells, 10(12), 3550. https://doi.org/10.3390/cells10123550

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PXR Suppresses PPARα-Dependent HMGCS2 Gene Transcription by Inhibiting the Interaction between PPARα and PGC1α

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