High-content analysis of constitutive androstane receptor (CAR) translocation identifies mosapride citrate as a CAR agonist that represses gluconeogenesis.
CAR
Gluconeogenesis
High-content screening
Mosapride citrate
Nuclear translocation
Journal
Biochemical pharmacology
ISSN: 1873-2968
Titre abrégé: Biochem Pharmacol
Pays: England
ID NLM: 0101032
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
03
06
2019
accepted:
10
07
2019
pubmed:
16
7
2019
medline:
2
7
2020
entrez:
16
7
2019
Statut:
ppublish
Résumé
The constitutive androstane receptor (CAR) plays an important role in hepatic drug metabolism and detoxification but has recently been projected as a potential drug target for metabolic disorders due to its repression of lipogenesis and gluconeogenesis. Thus, identification of physiologically-relevant CAR modulators has garnered significant interest. Here, we adapted the previously characterized human CAR (hCAR) nuclear translocation assay in human primary hepatocytes (HPH) to a high-content format and screened an FDA-approved drug library containing 978 compounds. Comparison of hCAR nuclear translocation results with the Tox21 hCAR luciferase reporter assay database in 643 shared compounds revealed significant overlap between these two assays, with approximately half of hCAR agonists also mediating nuclear translocation. Further validation of these compounds in HPH and/or using published data from literature demonstrated that hCAR translocation exhibits a higher correlation with the induction of hCAR target genes, such as CYP2B6, than the luciferase assay. In addition, some CAR antagonists which repress CYP2B6 mRNA expression in HPH, such as sorafenib, rimonabant, and CINPA1, were found to translocate hCAR to the nucleus of HPH. Notably, both the translocation assay and the luciferase assay identified mosapride citrate (MOS), a gastroprokinetic agent that is known to reduce fasting blood glucose levels in humans, as a novel hCAR activator. Further studies with MOS in HPH uncovered that MOS can repress the expression of gluconeogenic genes and decrease glucose output from hepatocytes, providing a previously unidentified liver-specific mechanism by which MOS modulates blood glucose levels.
Identifiants
pubmed: 31306645
pii: S0006-2952(19)30268-0
doi: 10.1016/j.bcp.2019.07.013
pmc: PMC6833947
mid: NIHMS1057096
pii:
doi:
Substances chimiques
Benzamides
0
Constitutive Androstane Receptor
0
Morpholines
0
Receptors, Cytoplasmic and Nuclear
0
mosapride
I8MFJ1C0BY
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
224-236Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM121550
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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