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dc.contributor.authorLi, Zhihui
dc.contributor.authorLi, Linhao
dc.contributor.authorHeyward, Scott
dc.contributor.authorMen, Shuaiqian
dc.contributor.authorXu, Meishu
dc.contributor.authorSueyoshi, Tatsuya
dc.contributor.authorWang, Hongbing
dc.date.accessioned2021-12-07T19:11:48Z
dc.date.available2021-12-07T19:11:48Z
dc.date.issued2021-12-01
dc.identifier.urihttp://hdl.handle.net/10713/17307
dc.description.abstractPhenobarbital (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.en_US
dc.description.sponsorshipNational Institute of General Medical Sciencesen_US
dc.description.urihttps://doi.org/10.3390/cells10123381en_US
dc.language.isoenen_US
dc.publisherMDPI AGen_US
dc.relation.ispartofCellsen_US
dc.subjectCARen_US
dc.subjectPhenobarbitalen_US
dc.subjectPXRen_US
dc.subjectSLC13A5en_US
dc.titlePhenobarbital induces slc13a5 expression through activation of pxr but not car in human primary hepatocytesen_US
dc.typeArticleen_US
dc.identifier.doi10.3390/cells10123381
dc.source.volume10
dc.source.issue12


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