Phenobarbital Induces SLC13A5 Expression through Activation of PXR but Not CAR in Human Primary Hepatocytes.
Base Sequence
Cells, Cultured
Constitutive Androstane Receptor
/ metabolism
Gene Expression Regulation
/ drug effects
Hepatocytes
/ drug effects
Humans
Introns
/ genetics
Metformin
/ pharmacology
Models, Biological
Phenobarbital
/ pharmacology
Pregnane X Receptor
/ antagonists & inhibitors
RNA, Messenger
/ genetics
Response Elements
/ genetics
Symporters
/ genetics
CAR
PXR
SLC13A5
phenobarbital
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
01 12 2021
01 12 2021
Historique:
received:
15
11
2021
revised:
26
11
2021
accepted:
29
11
2021
entrez:
24
12
2021
pubmed:
25
12
2021
medline:
7
1
2022
Statut:
epublish
Résumé
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 CAR-knockout 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
Identifiants
pubmed: 34943889
pii: cells10123381
doi: 10.3390/cells10123381
pmc: PMC8699749
pii:
doi:
Substances chimiques
Constitutive Androstane Receptor
0
Pregnane X Receptor
0
RNA, Messenger
0
SLC13A5 protein, human
0
Symporters
0
Metformin
9100L32L2N
Phenobarbital
YQE403BP4D
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM121550
Pays : United States
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