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Published on: April 24, 2021
Endoplasmic Reticulum Stress Increases Multidrug-resistance Protein 2 Expression and Mitigates Acute Liver Injury
Wen-Ge Huang1, Jun Wang1, Yu-Juan Liu1
1Department of Infectious Diseases, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China.
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.
Insights
Endoplasmic reticulum (ER) stress increases multidrug-resistance protein (MRP) 2 expression via nuclear factor kappa B (NF-κB) activation. This MRP2 upregulation protects against ER stress and acute liver injury.
Area of Science:
- Hepatology
- Molecular Biology
- Cellular Stress Response
Background:
- Multidrug-resistance protein (MRP) 2 is a hepatocyte transporter regulated by nuclear factor kappa B (NF-κB).
- Endoplasmic reticulum (ER) stress is linked to liver injury and NF-κB activation.
Purpose of the Study:
- Investigate the effect of ER stress on MRP2 expression.
- Determine MRP2's role in acute liver injury.
Main Methods:
- Utilized carbon tetrachloride (CCl4) and thapsigargin (TG) mouse models for acute liver injury and ER stress.
- Analyzed ER stress, MRP2 expression, and NF-κB activation in vivo and in vitro (LO2 cells).
- Assessed the impact of ER stress inhibitor (PBA) and NF-κB inhibitor (PDTC) on these markers.
Main Results:
- CCl4 and TG treatments significantly induced ER stress, MRP2 expression, and NF-κB activation.
- ER stress inhibition (PBA) reduced ER stress and MRP2 levels.
- NF-κB inhibition (PDTC) decreased NF-κB activation and MRP2 expression.
- Downregulation of MRP2 exacerbated CCl4-induced ER stress, apoptosis, and liver injury.
Conclusions:
- ER stress upregulates intrahepatic MRP2 protein expression through NF-κB activation.
- Increased MRP2 expression confers protection against ER stress and acute liver injury.
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