AI Article Synopsis
- The study focuses on how endoplasmic reticulum (ER) stress affects the expression of the multidrug-resistance protein (MRP) 2 in liver cells and its role in acute liver injury.
- Researchers used mouse models exposed to carbon tetrachloride (CCl4) and thapsigargin (TG) to demonstrate that both substances significantly induced ER stress, increased MRP2 expression, and activated NF-κB signaling.
- Inhibiting ER stress and NF-κB pathways reduced MRP2 expression and ER stress levels, suggesting that MRP2 serves as a protective response during liver injury by mitigating ER stress and associated cell damage.
Article 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 (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.
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| http://dx.doi.org/10.2174/1566524020666200124102411 | DOI Listing |
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