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 (P < 0.05). Pretreatment with ER stress inhibitor 4-
phenyl butyric 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.