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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2019.1
- 수록면
- 1,045 - 1,053 (9page)
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Purpose: To explore the molecular mechanism of the upregulation of multidrug resistance-associated protein 4 (MRP4) in cholestasis. Materials and Methods: The mRNA and protein levels of MRP4 in liver samples from cholestatic patients were determined byquantitative real-time PCR and Western blot. In human hepatoma HepG2 cells, electrophoretic mobility shift assay (EMSA) wasused to determine the affinity of nuclear factor-E2-related factor (Nrf2) binding to MRP4 promoter. Dual-luciferase reporter assaywas used to detect the binding of tumor necrosis factor α (TNFα) to the promotor of E2F1. The bile duct ligation mouse models wereestablished using male C57BL/6 mice. Results: The mRNA and protein levels of MRP4 were significantly increased in cholestatic patients. TNFα treatment induced theexpression of MRP4 and Nrf2 and enhanced cell nuclear extract binding activity to MRP4 promoter, as demonstrated by EMSA. Nrf2knockdown reduced MRP4 mRNA levels in both HepG2 and Hep-3B cells. In addition, TNFα increased Rb phosphorylation and expressionof MRP4 and Nrf2 and activated E2F1 and phosphorylated p38 in HepG2 and Hep-3B cells. These effects were markedly inhibitedby pretreatment with E2F1 siRNA. Dual-luciferase reporter assay validated that TNFα induces the transcription of E2F1. Furthermore,the expression of MRP4, Nrf2, E2F1, and p-p38 proteins was improved with treatment of TNFα in a mouse model ofcholestasis. E2F1 siRNA lentivirus or SB 203580 (p38 inhibitor) inhibited these positive effects. Conclusion: Our findings indicated that TNFα induces hepatic MRP4 expression through activation of the p38-E2F1-Nrf2 signalingpathway in human obstructive cholestasis.
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참고문헌 (30)
참고문헌 신청
Miszczuk GS / 2019 / Adaptive downregulation of Cl-/HCO3-exchange activity in rat hepatocytes under experimental obstructive cholestasis / PLoS One 14:e0212215
Wagner M / 2005 / Transcriptional regulation of hepatobiliary transport systems in health and disease : implications for a rationale approach to the treatment of intrahepatic cholestasis / Ann Hepatol 4:77~99
Zollner G / 2006 / Role of nuclear receptors in the adaptive response to bile acids and cholestasis : pathogenetic and therapeutic considerations / Mol Pharm 3:231~251
Wagner M / 2009 / New molecular insights into the mechanisms of cholestasis / J Hepatol 51:565~580
Schuetz JD / 1999 / MRP4 : a previously unidentified factor in resistance to nucleoside-based antiviral drugs / Nat Med 5:1048~1051
Wagner M / 2005 / Transcriptional regulation of hepatobiliary transport systems in health and disease : implications for a rationale approach to the treatment of intrahepatic cholestasis / Ann Hepatol 4:77~99
Zollner G / 2006 / Role of nuclear receptors in the adaptive response to bile acids and cholestasis : pathogenetic and therapeutic considerations / Mol Pharm 3:231~251
Wagner M / 2009 / New molecular insights into the mechanisms of cholestasis / J Hepatol 51:565~580
Schuetz JD / 1999 / MRP4 : a previously unidentified factor in resistance to nucleoside-based antiviral drugs / Nat Med 5:1048~1051
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