Tanshinone IIA prevents rifampicin-induced liver injury by regulating BSEP/NTCP expression via epigenetic activation of NRF2.
Liver Int
; 40(1): 141-154, 2020 01.
Article
em En
| MEDLINE
| ID: mdl-31571363
ABSTRACT
BACKGROUND & AIMS:
Rifampicin (RFP)-induced cholestatic liver injury is characterized by impaired hepatic bile acid (BA) transport. Bile salt efflux pump (BSEP) and Na+/taurocholate cotransporter (NTCP) are the major BA transporters. However, little is known about the mechanisms underlying these transporters.METHODS:
The role of tanshinone IIA (TAN IIA) in preventing RFP-induced liver injury was evaluated in vitro and in vivo, based on the regulatory mechanism of nuclear factor erythroid 2-related factor 2 (NRF2)-BSEP/NTCP signalling. The epigenetic induction of NRF2 by TAN IIA was investigated as well as the influence on BSEP and NTCP transcriptional activation and NRF2 DNA-binding ability.RESULTS:
TAN IIA strongly induced BSEP and NTCP expression in hepatocytes. NRF2 knockdown abrogated the induction. We found two NRF2 binding sites on the human BSEP promoter, called musculoaponeurotic fibrosarcoma recognition elements (MAREs), and one MARE on the NTCP promoter. Human BSEP and NTCP promoter luciferase reporter gene plasmids were stimulated by NRF2. Mutations of the predicted MAREs abolished NRF2 transcriptional activation. TAN IIA induced the expression of ten-eleven translocation 2 (TET2) to mediate the demethylation of NRF2, which promoted NRF2 DNA-binding on the BSEP and NTCP promoters and their transcriptional activation. Finally, in vivo, Nrf2 played an important role in RFP-induced liver injury (more serious liver injury in Nrf2-/- mice), and TAN IIA prevented it.CONCLUSIONS:
These results indicate that NRF2 regulates the target transporters BSEP and NTCP, depending on the DNA demethylation by TET2. Pharmacological activation of NRF2 by TAN IIA may be beneficial for RFP-induced liver injury.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Rifampina
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Transportadores de Ânions Orgânicos Dependentes de Sódio
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Simportadores
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Abietanos
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Epigênese Genética
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Fator 2 Relacionado a NF-E2
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Doença Hepática Crônica Induzida por Substâncias e Drogas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
/
Humans
/
Male
Idioma:
En
Revista:
Liver Int
Assunto da revista:
GASTROENTEROLOGIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China