Endoplasmic reticulum stress increases multidrug-resistance protein 2 expression and mitigates acute liver injury

BACKGROUND: Multidrug-resistance protein (MRP) 2 is a key membrane transporter that is expressed on hepatocytes and regulated by nuclear factor kappa B (NF-kappaB). Interestingly, endoplasmic reticulum (ER) stress is closely associated with liver injury and the activation of NF-kappaB 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-kappaB 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-kappaB inhibitor) significantly inhibited CCl4-induced NF-kappaB 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-kappaB. This increase in MRP2 expression mitigates ER stress and acute liver injury.