{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T13:50:28Z","timestamp":1767016228750,"version":"build-2065373602"},"reference-count":53,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T00:00:00Z","timestamp":1623110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","award":["20 0990 Pj"],"award-info":[{"award-number":["20 0990 Pj"]}],"id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001862","name":"Svenska Forskningsr\u00e5det Formas","doi-asserted-by":"publisher","award":["2018-00738"],"award-info":[{"award-number":["2018-00738"]}],"id":[{"id":"10.13039\/501100001862","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2018-03238"],"award-info":[{"award-number":["2018-03238"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Horizon 2020","award":["857394"],"award-info":[{"award-number":["857394"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Membranes"],"abstract":"<jats:p>Multidrug resistance proteins (MRPs), members of the ATP-binding cassette transporter (ABC transporter) family, are pivotal for transporting endo- and xenobiotics, which confer resistance to anticancer agents and contribute to the clearance of oxidative products. However, their function in many biological processes is still unclear. We investigated the role of an evolutionarily conserved MRP in metabolic homeostasis by knocking down the expression of Drosophila multidrug-resistance like protein 1 (MRP) in several tissues involved in regulating metabolism, including the gut, fat body, and Malpighian tubules. Interestingly, only suppression of MRP in the Malpighian tubules, the functional equivalent to the human kidney, was sufficient to cause abnormal lipid accumulation and disrupt feeding behavior. Furthermore, reduced Malpighian tubule MRP expression resulted in increased Hr96 (homolog of human pregnane X receptor) expression. Hr96 is known to play a role in detoxification and lipid metabolism processes. Reduced expression of MRP in the Malpighian tubules also conveyed resistance to oxidative stress, as well as reduced normal levels of reactive oxygen species in adult flies. This study reveals that an evolutionarily conserved MRP is required in Drosophila Malpighian tubules for proper metabolic homeostasis.<\/jats:p>","DOI":"10.3390\/membranes11060432","type":"journal-article","created":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T12:08:55Z","timestamp":1623154135000},"page":"432","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Multidrug Resistance Like Protein 1 Activity in Malpighian Tubules Regulates Lipid Homeostasis in Drosophila"],"prefix":"10.3390","volume":"11","author":[{"given":"Wen","family":"Liu","sequence":"first","affiliation":[{"name":"Functional Pharmacology, Department of Neuroscience, Uppsala University, 751 24 Uppsala, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Cao","sequence":"additional","affiliation":[{"name":"Functional Pharmacology, Department of Neuroscience, Uppsala University, 751 24 Uppsala, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moses","family":"Kimari","sequence":"additional","affiliation":[{"name":"Functional Pharmacology, Department of Neuroscience, Uppsala University, 751 24 Uppsala, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georgios","family":"Maronitis","sequence":"additional","affiliation":[{"name":"Functional Pharmacology, Department of Neuroscience, Uppsala University, 751 24 Uppsala, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Williams","sequence":"additional","affiliation":[{"name":"Functional Pharmacology, Department of Neuroscience, Uppsala University, 751 24 Uppsala, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helgi B","family":"Schi\u00f6th","sequence":"additional","affiliation":[{"name":"Functional Pharmacology, Department of Neuroscience, Uppsala University, 751 24 Uppsala, Sweden"},{"name":"Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"482","DOI":"10.3109\/03602531003654915","article-title":"Regulation of hepatic ABCC transporters by xenobiotics and in disease states","volume":"42","author":"Gu","year":"2010","journal-title":"Drug Metab. Rev."},{"doi-asserted-by":"crossref","unstructured":"Keppler, D. (2011). Multidrug resistance proteins (MRPs, ABCCs): Importance for pathophysiology and drug therapy. Handb. Exp. Pharmacol., 299\u2013323.","key":"ref_2","DOI":"10.1007\/978-3-642-14541-4_8"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.taap.2004.10.012","article-title":"Multidrug resistance proteins: Role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense","volume":"204","author":"Leslie","year":"2005","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"27","DOI":"10.2174\/1567201043480036","article-title":"The role of ABC transporters in drug resistance, metabolism and toxicity","volume":"1","author":"Glavinas","year":"2004","journal-title":"Curr. Drug Deliv."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/j.febslet.2005.12.036","article-title":"Substrate recognition and transport by multidrug resistance protein 1 (ABCC1)","volume":"580","author":"Deeley","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"352ra109","DOI":"10.1126\/scitranslmed.aaf9074","article-title":"ABCC1 confers tissue-specific sensitivity to cortisol versus corticosterone: A rationale for safer glucocorticoid replacement therapy","volume":"8","author":"Nixon","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1023\/A:1008036015156","article-title":"A new aspect on glutathione-associated biological function of MRP\/GS-X pump and its gene expression","volume":"27","author":"Ishikawa","year":"1998","journal-title":"Cytotechnology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/S0005-2736(99)00168-6","article-title":"Structural, mechanistic and clinical aspects of MRP1","volume":"1461","author":"Hipfner","year":"1999","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1038\/nm1197-1275","article-title":"Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein","volume":"3","author":"Wijnholds","year":"1997","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/j.jdiacomp.2016.02.002","article-title":"Multidrug resistance associated protein-1 (MRP1) deficiency attenuates endothelial dysfunction in diabetes","volume":"30","author":"Neuser","year":"2016","journal-title":"J. Diabetes Complicat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1111\/j.1478-3231.2008.01889.x","article-title":"Expression of multidrug resistance-associated protein 1 in hepatocellular carcinoma is associated with a more aggressive tumour phenotype and may reflect a progenitor cell origin","volume":"28","author":"Komuta","year":"2008","journal-title":"Liver Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2174\/187231208783478425","article-title":"Renal and hepatic transporter expression in type 2 diabetic rats","volume":"2","author":"Nowicki","year":"2008","journal-title":"Drug Metab. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1080\/03602530500205275","article-title":"Function and regulation of multidrug resistance proteins (MRPs) in the renal elimination of organic anions","volume":"37","author":"Masereeuw","year":"2005","journal-title":"Drug Metab. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1046\/j.1471-4159.2001.00101.x","article-title":"The multidrug resistance protein MRP1 mediates the release of glutathione disulfide from rat astrocytes during oxidative stress","volume":"76","author":"Hirrlinger","year":"2001","journal-title":"J. Neurochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"30880","DOI":"10.1074\/jbc.R114.609248","article-title":"Multidrug resistance protein 1 (MRP1, ABCC1), a \u201cmultitasking\u201d ATP-binding cassette (ABC) transporter","volume":"289","author":"Cole","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1208\/s12248-015-9757-1","article-title":"Multidrug Resistance Proteins (MRPs) and Cancer Therapy","volume":"17","author":"Zhang","year":"2015","journal-title":"AAPS J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1002\/jbt.21796","article-title":"Altered Hepatic Transport by Fetal Arsenite Exposure in Diet-Induced Fatty Liver Disease","volume":"30","author":"Ditzel","year":"2016","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.lfs.2011.05.005","article-title":"Role of high-fat diet in regulation of gene expression of drug metabolizing enzymes and transporters","volume":"89","author":"Ghose","year":"2011","journal-title":"Life Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1515\/bc.2011.052","article-title":"Increased expression of the multidrug resistance-associated protein 1 (MRP1) in kidney glomeruli of streptozotocin-induced diabetic rats","volume":"392","author":"Quezada","year":"2011","journal-title":"Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.1210\/en.2015-2006","article-title":"Dibutyl Phthalate Exposure Disrupts Evolutionarily Conserved Insulin and Glucagon-Like Signaling in Drosophila Males","volume":"157","author":"Williams","year":"2016","journal-title":"Endocrinology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1016\/S0960-9822(03)00375-0","article-title":"Dual origin of the renal tubules in Drosophila: Mesodermal cells integrate and polarize to establish secretory function","volume":"13","author":"Denholm","year":"2003","journal-title":"Curr. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"D744","DOI":"10.1093\/nar\/gks1141","article-title":"FlyAtlas: Database of gene expression in the tissues of Drosophila melanogaster","volume":"41","author":"Robinson","year":"2013","journal-title":"Nucleic Acids Res."},{"doi-asserted-by":"crossref","unstructured":"Pfeiffenberger, C., Lear, B.C., Keegan, K.P., and Allada, R. (2010). Locomotor activity level monitoring using the Drosophila Activity Monitoring (DAM) System. Cold Spring Harb. Protoc., 2010.","key":"ref_23","DOI":"10.1101\/pdb.prot5518"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4560","DOI":"10.1038\/ncomms5560","article-title":"Automated monitoring and quantitative analysis of feeding behaviour in Drosophila","volume":"5","author":"Itskov","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/ng2049","article-title":"Using FlyAtlas to identify better Drosophila melanogaster models of human disease","volume":"39","author":"Chintapalli","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.cmet.2009.10.010","article-title":"The DHR96 nuclear receptor controls triacylglycerol homeostasis in Drosophila","volume":"10","author":"Sieber","year":"2009","journal-title":"Cell Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S1665-2681(19)32136-2","article-title":"New concepts of mechanisms of intestinal cholesterol absorption","volume":"2","author":"Wang","year":"2003","journal-title":"Ann. Hepatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1124\/jpet.117.243584","article-title":"Xenobiotic Nuclear Receptors Pregnane X Receptor and Constitutive Androstane Receptor Regulate Antiretroviral Drug Efflux Transporters at the Blood-Testis Barrier","volume":"363","author":"Hoque","year":"2017","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1097\/01.qai.0000181280.68046.23","article-title":"Role of lymphocyte multidrug resistance protein 1 in HIV infection: Expression, function, and consequences of inhibition","volume":"40","author":"Lucia","year":"2005","journal-title":"JAIDS J. Acquir. Immune Defic. Syndr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1007\/s11064-006-9194-8","article-title":"Paraquat-induced oxidative stress in drosophila melanogaster: Effects of melatonin, glutathione, serotonin, minocycline, lipoic acid and ascorbic acid","volume":"31","author":"Bonilla","year":"2006","journal-title":"Neurochem. Res."},{"doi-asserted-by":"crossref","unstructured":"Huang, H., Lu-Bo, Y., and Haddad, G.G. (2014). A Drosophila ABC transporter regulates lifespan. PLoS Genet., 10.","key":"ref_31","DOI":"10.1371\/journal.pgen.1004844"},{"doi-asserted-by":"crossref","unstructured":"Kuzin, B.A., Nikitina, E.A., Cherezov, R.O., Vorontsova, J.E., Slezinger, M.S., Zatsepina, O.G., Simonova, O.B., Enikolopov, G.N., and Savvateeva-Popova, E.V. (2014). Combination of hypomorphic mutations of the Drosophila homologues of aryl hydrocarbon receptor and nucleosome assembly protein family genes disrupts morphogenesis, memory and detoxification. PLoS ONE, 9.","key":"ref_32","DOI":"10.1371\/journal.pone.0094975"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.freeradbiomed.2015.06.020","article-title":"Mechanisms and functions of Nrf2 signaling in Drosophila","volume":"88","author":"Pitoniak","year":"2015","journal-title":"Free Radic Biol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3389\/fnmol.2019.00086","article-title":"Drosophila Nrf2\/Keap1 Mediated Redox Signaling Supports Synaptic Function and Longevity and Impacts on Circadian Activity","volume":"12","author":"Spiers","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.bbalip.2004.12.007","article-title":"Function of prokaryotic and eukaryotic ABC proteins in lipid transport","volume":"1733","author":"Pohl","year":"2005","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1242\/dev.118.2.401","article-title":"Targeted gene expression as a means of altering cell fates and generating dominant phenotypes","volume":"118","author":"Brand","year":"1993","journal-title":"Development"},{"doi-asserted-by":"crossref","unstructured":"Soderberg, J.A., Birse, R.T., and Nassel, D.R. (2011). Insulin production and signaling in renal tubules of Drosophila is under control of tachykinin-related peptide and regulates stress resistance. PLoS ONE, 6.","key":"ref_37","DOI":"10.1371\/journal.pone.0019866"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1254\/jphs.10145FP","article-title":"Multidrug resistance protein transporter and Ins(1,4,5)P(3)-sensitive Ca(2)+-signaling involved in adenosine triphosphate export via Gq protein-coupled NK(2)-receptor stimulation with neurokinin A","volume":"114","author":"Sun","year":"2010","journal-title":"J. Pharmacol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1242\/jcs.112.3.415","article-title":"The human multidrug resistance protein MRP1 translocates sphingolipid analogs across the plasma membrane","volume":"112","author":"Raggers","year":"1999","journal-title":"J. Cell Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S0005-2736(98)00049-2","article-title":"Evidence for a role of the multidrug resistance protein (MRP) in the outward translocation of NBD-phospholipids in the erythrocyte membrane","volume":"1372","author":"Kamp","year":"1998","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1038\/nm.2049","article-title":"Foxo1 integrates insulin signaling with mitochondrial function in the liver","volume":"15","author":"Cheng","year":"2009","journal-title":"Nat. Med."},{"doi-asserted-by":"crossref","unstructured":"Sengupta, N., Reardon, D.C., Gerard, P.D., and Baldwin, W.S. (2017). Exchange of polar lipids from adults to neonates in Daphnia magna: Perturbations in sphingomyelin allocation by dietary lipids and environmental toxicants. PLoS ONE, 12.","key":"ref_42","DOI":"10.1371\/journal.pone.0178131"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.tox.2011.12.014","article-title":"Hepatocellular hypertrophy and cell proliferation in Sprague-Dawley rats from dietary exposure to potassium perfluorooctanesulfonate results from increased expression of xenosensor nuclear receptors PPARalpha and CAR\/PXR","volume":"293","author":"Elcombe","year":"2012","journal-title":"Toxicology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"18831","DOI":"10.1073\/pnas.0909731106","article-title":"Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease","volume":"106","author":"Dong","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2908","DOI":"10.1074\/jbc.M109326200","article-title":"Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor","volume":"277","author":"Kast","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.lfs.2008.11.021","article-title":"Multidrug-resistance-associated protein plays a protective role in menadione-induced oxidative stress in endothelial cells","volume":"84","author":"Takahashi","year":"2009","journal-title":"Life Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1248\/bpb.b12-00069","article-title":"Multidrug resistance associated protein 1 together with glutathione plays a protective role against 4-hydroxy-2-nonenal-induced oxidative stress in bovine aortic endothelial cells","volume":"35","author":"Takahashi","year":"2012","journal-title":"Biol. Pharm. Bull."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.molmed.2004.09.003","article-title":"Nrf2-Keap1 defines a physiologically important stress response mechanism","volume":"10","author":"Motohashi","year":"2004","journal-title":"Trends Mol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.devcel.2007.12.002","article-title":"Keap1\/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila","volume":"14","author":"Sykiotis","year":"2008","journal-title":"Dev. Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.taap.2008.10.017","article-title":"Sequencing and characterization of mixed function monooxygenase genes CYP1A1 and CYP1A2 of Mink (Mustela vison) to facilitate study of dioxin-like compounds","volume":"234","author":"Zhang","year":"2009","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1124\/dmd.112.045112","article-title":"Coordinated regulation of hepatic phase I and II drug-metabolizing genes and transporters using AhR-, CAR-, PXR-, PPARalpha-, and Nrf2-null mice","volume":"40","author":"Aleksunes","year":"2012","journal-title":"Drug Metab. Dispos."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1124\/dmd.107.015974","article-title":"Importance of hepatic induction of constitutive androstane receptor and other transcription factors that regulate xenobiotic metabolism and transport","volume":"35","author":"Petrick","year":"2007","journal-title":"Drug Metab. Dispos."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1124\/dmd.105.003798","article-title":"Induction of the multidrug resistance-associated protein family of transporters by chemical activators of receptor-mediated pathways in mouse liver","volume":"33","author":"Maher","year":"2005","journal-title":"Drug Metab. Dispos."}],"container-title":["Membranes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0375\/11\/6\/432\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:12:11Z","timestamp":1760163131000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0375\/11\/6\/432"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,8]]},"references-count":53,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["membranes11060432"],"URL":"https:\/\/doi.org\/10.3390\/membranes11060432","relation":{},"ISSN":["2077-0375"],"issn-type":[{"type":"electronic","value":"2077-0375"}],"subject":[],"published":{"date-parts":[[2021,6,8]]}}}