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Endoplasmic Reticulum Stress Increases Multidrug-resistance Protein 2 Expression and Mitigates Acute Liver Injury

Author(s):

Wen-Ge Huang, Jun Wang, Yu-Juan Liu, Hong-Xia Wang, Si-Zhen Zhou, Huan Chen, Fang-Wan Yang, Ying Li, Yu Yi and Yi-Huai He*   Pages 1 - 10 ( 10 )

Abstract:


Background: Multidrug-resistance protein (MRP) 2 is a key membrane transporter that is expressed on hepatocytes and regulated by nuclear factor kappa B (NF-κB). Interestingly, endoplasmic reticulum (ER) stress is closely associated with liver injury and the activation of NF-κB signaling.

Objective: Here, we investigated the impact of ER stress on MRP2 expression and the functional involvement of MRP2 in acute liver injury.

Methods: ER stress, MRP2 expression, and hepatocyte injury were analyzed in a carbon tetrachloride (CCl4)-induced mouse model of acute liver injury and in a thapsigargin (TG)-induced model of ER stress.

Results: CCl4 and TG induced significant ER stress, MRP2 protein expression and NF-κB activation in mice and LO2 cells, respectively (P < 0.05). Pretreatment with ER stress inhibitor 4-phenylbutyric acid (PBA) significantly mitigated CCl4 and TG-induced ER stress and MRP2 protein expression (P < 0.05). Moreover, pretreatment with pyrrolidine dithiocarbamic acid (PDTC; NF-κB inhibitor) significantly inhibited CCl4-induced NF-κB activation and reduced MRP2 protein expression (1±0.097 vs. 0.623±0.054; P < 0.05). Furthermore, hepatic downregulation of MRP2 expression significantly increased CCl4-induced ER stress, apoptosis, and liver injury.

Conclusion: ER stress enhances intrahepatic MRP2 protein expression by activating NF-κB. This increase in MRP2 expression mitigates ER stress and acute liver injury.

Keywords:

Multidrug-resistance protein 2, Endoplasmic reticulum stress, Apoptosis, Necroptosis, Nuclear factor kappa B, Acute liver injury

Affiliation:

Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou



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