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Changes of Organic Anion Transporter MRP4 and Related Nuclear Receptors in Human Obstructive Cholestasis

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Journal of Gastrointestinal Surgery Aims and scope

Abstract

Background

Hepatic multidrug resistance-associated protein 4 (Mrp4) levels are low, but increase markedly in rodent cholestatic liver. Nuclear receptors (NRs) are essential for regulating Mrp4 expression in cholestasis models. However, information about MRP4 and related NRs, including constitutive androstane receptor (CAR), pregnane X receptor (PXR), and retinoic X receptor-α (RXRα), is relatively lacking in human obstructive cholestasis. We collected liver samples from patients with obstructive cholestasis or without liver disease and investigated the expression of MRP4 and NRs CAR, PXR, and RXRα by semi-quantitative RT-PCR, Western blot and immunostaining assays.

Results

MRP4 mRNA/protein levels were markedly increased in obstructive cholestasis. Concentration of serum total bile acids (TBA) was significantly correlated with MRP4 protein in cholestasis samples (P < 0.01). PXR and RXRα mRNA/protein levels were significantly increased in obstructive cholestasis. CAR mRNA levels were unchanged while protein levels were markedly induced in obstructive cholestasis. There was a statistically positive correlation between MRP4 mRNA and CAR protein (P < 0.05), suggesting that CAR may activate transcription of MRP4 genes by its nuclear translocation.

Conclusion

Hepatic MRP4 levels were dramatically induced in human obstructive cholestasis, which may reduce liver injury by increasing efflux of toxic bile acids from hepatocytes into blood.

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Acknowledgment

This work was supported by the State Foundation for Natural Sciences of the People’s Republic of China (30570842, 30900678, 81070320, and CSTC, 2007BA5030).

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Authors and Affiliations

  1. Institute of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Jin Chai, Xiaoping Wu, Yanmei Zhang, Lei Chen, Zhi-Hong Peng, Tianli Xiao, Rongquan Wang & Wensheng Chen

  2. Department of Abdominal Surgery, Daping Hospital, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Donglin Luo

  3. Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Huaizhi Wang & Yu He

  4. Laboratory and Education Center, College of Basic Medical Science, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Qiong Li

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  1. Jin Chai
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Correspondence to Wensheng Chen.

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Jin Chai and Donglin Luo contributed equally to this study.

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Chai, J., Luo, D., Wu, X. et al. Changes of Organic Anion Transporter MRP4 and Related Nuclear Receptors in Human Obstructive Cholestasis. J Gastrointest Surg 15, 996–1004 (2011). https://doi.org/10.1007/s11605-011-1473-2

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