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Tanshinone IIA prevents rifampicin‐induced liver injury by regulating BSEP/NTCP expression via epigenetic activation of NRF2
Author(s) -
Yang Yujie,
Liu Lei,
Zhang Xiqian,
Jiang Xuehua,
Wang Ling
Publication year - 2020
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.14262
Subject(s) - bile salt export pump , epigenetics , liver injury , dna demethylation , chemistry , promoter , demethylation , multidrug resistance associated protein 2 , reporter gene , dna methylation , microbiology and biotechnology , pharmacology , transporter , gene expression , biology , gene , biochemistry , atp binding cassette transporter
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.