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    Phenobarbital induces slc13a5 expression through activation of pxr but not car in human primary hepatocytes

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    Author
    Li, Zhihui
    Li, Linhao
    Heyward, Scott
    Men, Shuaiqian
    Xu, Meishu
    Sueyoshi, Tatsuya
    Wang, Hongbing
    Date
    2021-12-01
    Journal
    Cells
    Publisher
    MDPI AG
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.3390/cells10123381
    Abstract
    Phenobarbital (PB), a widely used antiepileptic drug, is known to upregulate the expression of numerous drug-metabolizing enzymes and transporters in the liver primarily via activation of the constitutive androstane receptor (CAR, NR1I3). The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter, plays an important role in intracellular citrate homeostasis that is associated with a number of metabolic syndromes and neurological disorders. Here, we show that PB markedly elevates the expression of SLC13A5 through a pregnane X receptor (PXR)dependent but CAR-independent signaling pathway. In human primary hepatocytes, the mRNA and protein expression of SLC13A5 was robustly induced by PB treatment, while genetic knockdown or pharmacological inhibition of PXR significantly attenuated this induction. Utilizing genetically modified HepaRG cells, we found that PB induces SLC13A5 expression in both wild type and CARknockout HepaRG cells, whereas such induction was fully abolished in the PXR-knockout HepaRG cells. Mechanistically, we identified and functionally characterized three enhancer modules located upstream from the transcription start site or introns of the SLC13A5 gene that are associated with the regulation of PXR-mediated SLC13A5 induction. Moreover, metformin, a deactivator of PXR, dramatically suppressed PB-mediated induction of hepatic SLC13A5 as well as its activation of the SLC13A5 luciferase reporter activity via PXR. Collectively, these data reveal PB as a potent inducer of SLC13A5 through the activation of PXR but not CAR in human primary hepatocytes. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
    Sponsors
    National Institute of General Medical Sciences
    Keyword
    CAR
    Phenobarbital
    PXR
    SLC13A5
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17307
    ae974a485f413a2113503eed53cd6c53
    10.3390/cells10123381
    Scopus Count
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