Login Register Cart 0
Generic placeholder image

Current Molecular Medicine

Editor-in-Chief

ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

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*

Volume 20, Issue 7, 2020

Page: [548 - 557] Pages: 10

DOI: 10.2174/1566524020666200124102411

Price: $65

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.

Keywords: Multidrug-resistance protein 2, endoplasmic reticulum stress, apoptosis, necroptosis, nuclear factor kappa B, acute liver injury.

« Previous Next »
[1]
Furuyama T, Kudo A, Matsumura S, et al. Preoperative direct bilirubin to prothrombin time ratio index to prevent liver failure after minor hepatectomy. J Hepatobiliary Pancreat Sci 2016; 23(12): 763-70.
[http://dx.doi.org/10.1002/jhbp.400] [PMID: 27717165]
[2]
Sticova E, Jirsa M. New insights in bilirubin metabolism and their clinical implications. World J Gastroenterol 2013; 19(38): 6398-407.
[http://dx.doi.org/10.3748/wjg.v19.i38.6398] [PMID: 24151358]
[3]
Wang X, Zheng L, Wu J, et al. Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease. Mol Med Rep 2017; 15(6): 3459-66.
[http://dx.doi.org/10.3892/mmr.2017.6435] [PMID: 28393244]
[4]
Kamisako T, Leier I, Cui Y, et al. Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2. Hepatology 1999; 30(2): 485-90.
[http://dx.doi.org/10.1002/hep.510300220] [PMID: 10421658]
[5]
Park SW, Jun CH, Choi SK, Kim HJ, Kim GE. Hepatobiliary and Pancreatic: A black liver of Dubin-Johnson syndrome. J Gastroenterol Hepatol 2018; 33(3): 562.
[http://dx.doi.org/10.1111/jgh.14036] [PMID: 29469235]
[6]
Tsujii H, König J, Rost D, Stöckel B, Leuschner U, Keppler D. Exon-intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin-Johnson syndrome. Gastroenterology 1999; 117(3): 653-60.
[http://dx.doi.org/10.1016/S0016-5085(99)70459-2] [PMID: 10464142]
[7]
Yang FW, Fu Y, Li Y, et al. Prostaglandin E1 protects hepatocytes against endoplasmic reticulum stress-induced apoptosis via protein kinase A-dependent induction of glucose-regulated protein 78 expression. World J Gastroenterol 2017; 23(40): 7253-64.
[http://dx.doi.org/10.3748/wjg.v23.i40.7253] [PMID: 29142472]
[8]
Hiss DC, Gabriels GA. Implications of endoplasmic reticulum stress, the unfolded protein response and apoptosis for molecular cancer therapy. Part I: targeting p53, Mdm2, GADD153/CHOP, GRP78/BiP and heat shock proteins. Expert Opin Drug Discov 2009; 4(8): 799-821.
[http://dx.doi.org/10.1517/17460440903052559] [PMID: 23496268]
[9]
Schmitz ML, Shaban MS, Albert BV, Gökçen A, Kracht M. The Crosstalk of Endoplasmic Reticulum (ER) Stress Pathways with NF-κB: Complex Mechanisms Relevant for Cancer, Inflammation and Infection. Biomedicines 2018; 6(2)E58
[http://dx.doi.org/10.3390/biomedicines6020058] [PMID: 29772680]
[10]
Hughes A, Oxford AE, Tawara K, Jorcyk CL, Oxford JT. Endoplasmic reticulum stress and unfolded protein response in cartilage pathophysiology; contributing factors to apoptosis and osteoarthritis. Int J Mol Sci 2017; 18(3)E665
[http://dx.doi.org/10.3390/ijms18030665] [PMID: 28335520]
[11]
Khan MF, Spurgeon S, von der Haar T. Origins of robustness in translational control via eukaryotic translation initiation factor (eIF) 2. J Theor Biol 2018; 445: 92-102.
[http://dx.doi.org/10.1016/j.jtbi.2018.02.020] [PMID: 29476830]
[12]
Hillary RF, FitzGerald U. A lifetime of stress: ATF6 in development and homeostasis. J Biomed Sci 2018; 25(1): 48.
[http://dx.doi.org/10.1186/s12929-018-0453-1] [PMID: 29801500]
[13]
Li LM, Lü SY, Li RJ. The Arabidopsis endoplasmic reticulum associated degradation pathways are involved in the regulation of heat stress response. Biochem Biophys Res Commun 2017; 487(2): 362-7.
[http://dx.doi.org/10.1016/j.bbrc.2017.04.066] [PMID: 28414129]
[14]
Eigner K, Filik Y, Mark F, et al. The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone. Sci Rep 2017; 7(1): 17498.
[http://dx.doi.org/10.1038/s41598-017-17888-9] [PMID: 29235576]
[15]
Xue M, Fu F, Ma Y, et al. The PERK arm of the unfolded protein response negatively regulates transmissible gastroenteritis virus replication by suppressing protein translation and promoting type i interferon production. J Virol 2018; 92(15): e00431-18.
[http://dx.doi.org/10.1128/JVI.00431-18] [PMID: 29769338]
[16]
Tavernier SJ, Osorio F, Vandersarren L, et al. Regulated IRE1-dependent mRNA decay sets the threshold for dendritic cell survival. Nat Cell Biol 2017; 19(6): 698-710.
[http://dx.doi.org/10.1038/ncb3518] [PMID: 28459443]
[17]
McLaughlin M, Alloza I, Quoc HP, Scott CJ, Hirabayashi Y, Vandenbroeck K. Inhibition of secretion of interleukin (IL)-12/IL-23 family cytokines by 4-trifluoromethyl-celecoxib is coupled to degradation via the endoplasmic reticulum stress protein HERP. J Biol Chem 2010; 285(10): 6960-9.
[http://dx.doi.org/10.1074/jbc.M109.056614] [PMID: 20054003]
[18]
Fan P, Tyagi AK, Agboke FA, Mathur R, Pokharel N, Jordan VC. Modulation of nuclear factor-kappa B activation by the endoplasmic reticulum stress sensor PERK to mediate estrogen-induced apoptosis in breast cancer cells. Cell Death Discov 2018; 4: 15.
[http://dx.doi.org/10.1038/s41420-017-0012-7] [PMID: 29531812]
[19]
Schoemaker MH, Gommans WM, Conde de la Rosa L, et al. Resistance of rat hepatocytes against bile acid-induced apoptosis in cholestatic liver injury is due to nuclear factor-kappa B activation. J Hepatol 2003; 39(2): 153-61.
[http://dx.doi.org/10.1016/S0168-8278(03)00214-9] [PMID: 12873810]
[20]
Preziosi M, Poddar M, Singh S, Monga SP. Hepatocyte Wnts are dispensable during diethylnitrosamine and carbon tetrachloride-induced injury and hepatocellular cancer. Gene Expr 2018; 18(3): 209-19.
[http://dx.doi.org/10.3727/105221618X15205148413587] [PMID: 29519268]
[21]
Weber LW, Boll M, Stampfl A. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol 2003; 33(2): 105-36.
[http://dx.doi.org/10.1080/713611034] [PMID: 12708612]
[22]
Sehgal P, Szalai P, Olesen C, et al. Inhibition of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase by thapsigargin analogs induces cell death via ER Ca2+ depletion and the unfolded protein response. J Biol Chem 2017; 292(48): 19656-73.
[http://dx.doi.org/10.1074/jbc.M117.796920] [PMID: 28972171]
[23]
Simmonds RC. Bioethics and animal use in programs of research, teaching, and testing.In: nd, Weichbrod RH, Thompson GAH, Norton JN, eds Management of animal care and use programs in research, education, and testing Boca Raton (FL). 2018; pp. pp. pp. 35-.
[24]
Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981; 1(5): 431-5.
[http://dx.doi.org/10.1002/hep.1840010511] [PMID: 7308988]
[25]
Tian RD, Chen YQ, He YH, et al. Phosphorylation of eIF2alpha mitigates endoplasmic reticulum stress and hepatocyte necroptosis in acute liver injury. Ann Hepatol 2019; 19(1): 79-87.
[PMID: 31548168]
[26]
Lippi G, Dipalo M, Musa R, et al. Evaluation of the analytical performances of the novel Beckman Coulter AU5800. Clin Biochem 2012; 45(6): 502-4.
[http://dx.doi.org/10.1016/j.clinbiochem.2012.01.015] [PMID: 22296728]
[27]
Qadri I, Iwahashi M, Kullak-Ublick GA, Simon FR. Hepatocyte nuclear factor (HNF) 1 and HNF4 mediate hepatic multidrug resistance protein 2 up-regulation during hepatitis C virus gene expression. Mol Pharmacol 2006; 70(2): 627-36.
[http://dx.doi.org/10.1124/mol.106.023499] [PMID: 16670373]
[28]
Qu X, Zhang Y, Zhang S, et al. Dysregulation of BSEP and MRP2 May Play an Important Role in Isoniazid-Induced Liver Injury via the SIRT1/FXR Pathway in Rats and HepG2 Cells. Biol Pharm Bull 2018; 41(8): 1211-8.
[http://dx.doi.org/10.1248/bpb.b18-00028] [PMID: 30068870]
[29]
Li M, Wang W, Soroka CJ, et al. NHERF-1 binds to Mrp2 and regulates hepatic Mrp2 expression and function. J Biol Chem 2010; 285(25): 19299-307.
[http://dx.doi.org/10.1074/jbc.M109.096081] [PMID: 20404332]
[30]
Hayashi H, Mizuno T, Horikawa R, et al. 4-Phenylbutyrate modulates ubiquitination of hepatocanalicular MRP2 and reduces serum total bilirubin concentration. J Hepatol 2012; 56(5): 1136-44.
[http://dx.doi.org/10.1016/j.jhep.2011.11.021] [PMID: 22245901]
[31]
Logan SM, Wu CW, Storey KB. The squirrel with the lagging eIF2: Global suppression of protein synthesis during torpor. Comp Biochem Physiol A Mol Integr Physiol 2019; 227: 161-71.
[http://dx.doi.org/10.1016/j.cbpa.2018.10.014] [PMID: 30343059]
[32]
Erffelinck ML, Goossens A. Review: Endoplasmic reticulum-associated degradation (ERAD)-dependent control of (Tri)terpenoid metabolism in plants. Planta Med 2018; 84(12-13): 874-80.
[http://dx.doi.org/10.1055/a-0635-8369] [PMID: 29906815]
[33]
Wong AK, Chao JT, Loewen CJ. Barriers to uniformity within the endoplasmic reticulum. Curr Opin Cell Biol 2014; 29: 31-8.
[http://dx.doi.org/10.1016/j.ceb.2014.03.007] [PMID: 24732434]
[34]
Kaneko M, Takahashi T, Niinuma Y, Nomura Y. Manganese superoxide dismutase is induced by endoplasmic reticulum stress through IRE1-mediated nuclear factor (NF)-kappaB and AP-1 activation. Biol Pharm Bull 2004; 27(8): 1202-6.
[http://dx.doi.org/10.1248/bpb.27.1202] [PMID: 15305022]
[35]
Mahadevan NR, Rodvold J, Almanza G, Pérez AF, Wheeler MC, Zanetti M. ER stress drives Lipocalin 2 upregulation in prostate cancer cells in an NF-κB-dependent manner. BMC Cancer 2011; 11: 229.
[http://dx.doi.org/10.1186/1471-2407-11-229] [PMID: 21649922]
[36]
Zhang J, Zhang M, Sun B, et al. Hyperammonemia enhances the function and expression of P-glycoprotein and Mrp2 at the blood-brain barrier through NF-κB. J Neurochem 2014; 131(6): 791-802.
[http://dx.doi.org/10.1111/jnc.12944] [PMID: 25200138]
[37]
Zhuang X, Li X, Zhang J, et al. Conditioned medium mimicking the tumor microenvironment augments chemotherapeutic resistance via ataxia telangiectasia mutated and nuclear factor-κB pathways in gastric cancer cells. Oncol Rep 2018; 40(4): 2334-42.
[http://dx.doi.org/10.3892/or.2018.6637] [PMID: 30106453]
[38]
Chai J, Cai SY, Liu X, et al. Canalicular membrane MRP2/ABCC2 internalization is determined by Ezrin Thr567 phosphorylation in human obstructive cholestasis. J Hepatol 2015; 63(6): 1440-8.
[http://dx.doi.org/10.1016/j.jhep.2015.07.016] [PMID: 26212029]
[39]
Xavier SA, Vilas-Boas R, Boal Carvalho P, Magalhães JT, Marinho CM, Cotter JB. Assessment of prognostic performance of albumin-bilirubin, child-pugh, and model for end-stage liver disease scores in patients with liver cirrhosis complicated with acute upper gastrointestinal bleeding. Eur J Gastroenterol Hepatol 2018; 30(6): 652-8.
[http://dx.doi.org/10.1097/MEG.0000000000001087] [PMID: 29438135]
[40]
Di Giacomo S, Briz O, Monte MJ, et al. Chemosensitization of hepatocellular carcinoma cells to sorafenib by β-caryophyllene oxide-induced inhibition of ABC export pumps. Arch Toxicol 2019; 93(3): 623-34.
[http://dx.doi.org/10.1007/s00204-019-02395-9] [PMID: 30659321]
[41]
Tocchetti GN, Domínguez CJ, Zecchinati F, et al. Inhibition of multidrug resistance-associated protein 2 (MRP2) activity by the contraceptive nomegestrol acetate in HepG2 and Caco-2 cells. Eur J Pharm Sci 2018; 122: 205-13.
[http://dx.doi.org/10.1016/j.ejps.2018.07.017] [PMID: 29981893]
[42]
Qu XY, Tao LN, Zhang SX, et al. The role of Ntcp, Oatp2, Bsep and Mrp2 in liver injury induced by Dioscorea bulbifera L. and Diosbulbin B in mice. Environ Toxicol Pharmacol 2017; 51: 16-22.
[http://dx.doi.org/10.1016/j.etap.2017.02.023] [PMID: 28262508]
[43]
Wrighton KH. Inactivating PTP1B upon ER stress. Nat Rev Mol Cell Biol 2012; 13(2): 62-3.
[http://dx.doi.org/10.1038/nrm3269] [PMID: 22218152]
[44]
Olivares S, Henkel AS. Hepatic Xbp1 gene deletion promotes endoplasmic reticulum stress-induced liver injury and apoptosis. J Biol Chem 2015; 290(50): 30142-51.
[http://dx.doi.org/10.1074/jbc.M115.676239] [PMID: 26504083]

Rights & Permissions Print Cite
Article Metrics
35
World Malaria Day
© 2024 Bentham Science Publishers | Privacy Policy