Characterization of organic anion transporter regulation, glutathione metabolism and bile formation in the obese Zucker rat
Abstract
Background/aims Alterations in hepatobiliary transporters may render fatty livers more vulnerable against various toxic insults.Methods We therefore studied expression and function of key organic anion transporters and their transactivators in 8-week-old obese Zucker rats, an established model for non-alcoholic fatty liver disease.Results Compared to their heterozygous littermates, obese animals showed a significant reduction in canalicular bile salt secretion, which was paralleled by significantly diminished Oatp2 mRNA and protein levels together with reduced nuclear HNF3beta, while expression of bile salt export pump, organic anion transporter (Oatp) 1 and multidrug resistance-associated protein (Mrp) 4 were unchanged. Impaired bile salt-independent bile flow in obese rats was associated with a 50% reduction of biliary secretion of the Mrp 2 model-substrates glutathione disulfide and S-(2,4-dinitrophenyl)glutathione. In line Mrp2 protein expression was reduced by 50% in obese rats.Conclusions Oatp2 and Mrp2 expression is decreased in fatty liver and may impair metabolism and biliary secretion of numerous xenobiotics. Reduction of bile salt secretion and absence of biliary GSH excretion may contribute to impaired bile flow and posthepatic disorders associated with biliary GSH depletion.
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Bile acid toxicity as a result of impaired hepatobiliary excretory function and functional (micro)cholestasis may also be involved in the pathogenesis of NASH.
“Interestingly, BA toxicity as result of impaired hepatobiliary excretory function18 19 and functional (micro)cholestasis20 may also be involved in the pathogenesis of NASH.12”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [19]
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“Decreased bile acid transporter expression renders fatty livers in ob/ob mice cholestatic Whether ob/ob mice are cholestatic, as recently reported for fa/fa Zucker rats, has not been investigated so far (Geier et al., 2005a).”
BackgroundMethodResultInfluentialBile acid signaling in MASLD: From pathogenesis to therapeutic applications
Simbrunner, B., Paternostro, R., Reiberger, T., & Trauner, M. (2025) · Hepatology · doi:10.1097/hep.0000000000001539 · Cited by 26 · see citing works
van Rhee, K. P., Smit, C., Wasmann, R. E., van der Linden, P. D., Wiezer, M. J., van Dongen, E. P. A., Krekels, E. H. J., Brüggemann, R. J. M., & Knibbe, C. A. J. (2022) · Clinical Pharmacokinetics · doi:10.1007/s40262-022-01130-5 · Cited by 20 · see citing works
“The absence of an influence of weight on bioavailability is in agreement with the observation that OATP1 function is unaffected in obese overfed rats [22].”
ResultZagorova, M., Prašnická, A., Kadová, Z., Doleželová, E., Kazdová, L., Cermanová, J., Rozkydalová, L., Hroch, M., Mokrý, J., & Mičuda, S. (2015) · Physiological Research · doi:10.33549/physiolres.933206 · Cited by 20 · see citing works
Severe jaundice following treatment with ezetimibe
Ritchie, S. R., Orr, D. W., & Black, P. (2008) · European Journal of Gastroenterology & Hepatology · doi:10.1097/meg.0b013e3282f1752d · Cited by 15 · see citing works
Persistent organic pollutants associate with liver disease in a Finnish general population sample
Hakkarainen, K., Rantakokko, P., Koponen, J. M., Ruokojärvi, P. H., Korkalainen, M., Salomaa, V. V., Jula, A., Männistö, S., Perola, M., Lundqvist, A., et al. (2023) · Liver International · doi:10.1111/liv.15645 · Cited by 14 · see citing works
Liao, G.-C., Jhuang, J.-H., & Yao, H. (2021) · Food & Function · doi:10.1039/d1fo00861g · Cited by 14 · see citing works
Tang, J., Fang, Q., Shao, R., Shen, J., He, J., Niu, D., & Lu, L. (2018) · Gene · doi:10.1016/j.gene.2018.05.122 · Cited by 12 · see citing works
Li, M., Huang, C., Chen, S.-H., Lee, C.-N., & Yao, H. (2022) · Food & Function · doi:10.1039/d1fo03597e · Cited by 12 · see citing works
Laddha, A. P., Dzielak, L., Lewis, C., Xue, R., & Manautou, J. E. (2024) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2024.167037 · Cited by 10 · see citing works
Dysregulation of Bile Acids in Patients with NAFLD
Zhang, X., & Deng, R. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.81474 · Cited by 10 · see citing works
“Consistently, a study with obese zucker rats showed that Bsep expression was not significantly altered in obese ZR rats compared to control rats [129].”
BackgroundResultInfluentialRole of miR-511 in the Regulation of OATP1B1 Expression by Free Fatty Acid
Peng, J. F., Liu, L., Guo, C., Liu, S. K., Chen, X. P., Huang, L. H., Xiang, H., Huang, Z. J., Yuan, H., & Yang, G. (2015) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2015.010 · Cited by 9 · see citing works
“OATP1B1 is an important drug transporter for human, and its expression is affected by inflammatory cytokines, hepatocyte growth factor, intrahepatic cholestasis and FFA (Geier et al., 2005; Keitel et al., 2005; Le Ve et al., 2009a; Le Vee et al., 2009b).”
BackgroundBertone, V., Tarantola, E., Ferrigno, A., Gringeri, E., Barni, S., Vairetti, M., & Freitas, I. (2011) · European Journal of Histochemistry · doi:10.4081/ejh.2011.e5 · Cited by 9 · see citing works
Melnyk, S., Korourian, S., Levy, J., Pavliv, O., Evans, T. T., & Hakkak, R. (2017) · Metabolites · doi:10.3390/metabo7020026 · Cited by 8 · see citing works
Pastor, C. M., Wissmeyer, M., & Millet, P. (2012) · Contrast Media & Molecular Imaging · doi:10.1002/cmmi.1511 · Cited by 8 · see citing works
“Because cholestatic fatty livers have a decreased expression of Oatp1a4 (17,18) and Mrp2 (17,19), we hypothesized that Gd–BOPTA would differently accumulate within cholestatic hepatocytes.”
BackgroundRegulation of Hepatobiliary Transporters during Liver Injury
Manautou, J. E., Campion, S. N., & Aleksunes, L. M. (2010) · Elsevier eBooks · doi:10.1016/b978-0-08-046884-6.01008-3 · Cited by 8 · see citing works
Pharmacokinetics of Hormonal Contraception in Individuals with Obesity: a Review
Ramanadhan, S., Jusko, W. J., & Edelman, A. B. (2020) · Current Obstetrics and Gynecology Reports · doi:10.1007/s13669-020-00284-y · Cited by 7 · see citing works
Effects of bile acid sequestration on hepatic steatosis in obese mice
Solı́s, N., Pizarro, M., Quintero, P., Arab, J. P., Riquelme, A. J., Padilla, O., Carrasco-Aviño, G., Pirola, C. J., Sookoian, S., & Arrese, M. A. (2014) · Annals of Hepatology · doi:10.1016/s1665-2681(19)30911-1 · Cited by 7 · see citing works
Pharmakokinetische Besonderheiten bei adipösen Patienten
Engeli, S., & May, M. (2014) · Adipositas - Ursachen Folgeerkrankungen Therapie · doi:10.1055/s-0037-1618844 · Cited by 6 · see citing works
“Daher muss bei adipösen Patienten bei vielen Xenobiotika von einer beeinträchtigten biliären Sekretionskapazität ausgegangen werden (41).”
BackgroundEzetimibe Increases Hepatic Iron Levels in Mice Fed a High-Fat Diet
Kishino, Y., Tanaka, Y., Ikeda, T., Yamamoto, K., Ogawa, H., Iwatani, Y., & Kamisako, T. (2013) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.113.203448 · Cited by 6 · see citing works
“The term NAFLD encompasses a broad spectrum of liver diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH).”
BackgroundInfluentialFu, R., Zhang, F., Fu, J., Li, Y., Zhu, X., Ding, Q., & Zhu, Y. Z. (2025) · Metabolism and Target Organ Damage · doi:10.20517/mtod.2025.163 · Cited by 6 · see citing works
Zhang, T., Calvier, E. A. M., Krekels, E. H. J., & Knibbe, C. A. J. (2025) · Pharmaceutical Research · doi:10.1007/s11095-025-03885-5 · Cited by 4 · see citing works
Regulation of Hepatobiliary Transporters During Liver Injury
Manautou, J. E., & Ghanem, C. I. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.95661-7 · Cited by 3 · see citing works
Steatosis Alters the Activity of Hepatocyte Membrane Transporters in Obese Rats
Pastor, C. M., & Vilgrain, V. (2021) · Cells · doi:10.3390/cells10102733 · Cited by 3 · see citing works
“Nevertheless, the Mrp3 expression is not increased in fa/fa livers [11,25], suggesting that a dysregulation might promote BOPTA transport without changing the transporter expression.”
BackgroundInfluentialMa, L., He, L., Wang, L., Li, L., Lin, X., & Pan, G. (2015) · European Journal of Drug Metabolism and Pharmacokinetics · doi:10.1007/s13318-015-0306-1 · Cited by 1 · see citing works
Damodaran, S., & Swaminathan, K. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-416045-3.00006-6 · Cited by 1 · see citing works
Donepudi, A. C. (2013) · doi:10.23860/diss-donepudi-ajay-chowdary-2013
“137 expression was significantly downregulated (Geier et al., 2005).”
Feng, T. T. Q. (2012) · TSpace (University of Toronto)
Besonderheiten der Pharmakotherapie adipöser Patienten
May, M., & Engeli, S. (2015) · CardioVasc · doi:10.1007/s15027-015-0638-4
Obesity and Its Impact on Drug Therapy
Neely, M. N., & Louie, S. G. (2011) · Clinical Pharmacokinetics · doi:10.2165/11597120-000000000-00000
THE IMPACT OF OBESITY ON PROTEINS INVOLVED IN DRUG METABOLISM
Al-Agili, M. (2017) · ERA: Education and Research Archive (University of Alberta) · doi:10.7939/r31n7z188
Impact of Maternal Inflammatory Conditions on the Expression of Drug Transporters
Ghoneim, R. H. (2016) · TSpace (University of Toronto)
Damodaran, S., & Swaminathan, K. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-817919-2.00005-x
Evaluation of blood mercury levels and a few biochemical marker levels in obese car painters of Iraq
Jawad, N. K., Numan, A. T., & Hanoon, Y. K. (2024) · Biomedicine · doi:10.51248/.v43i6.3549
“Obesity might impair the biliary excretion of methylmercury due to dysfunctional mechanisms and reduced levels of glutathione (17, 18).”
BackgroundRegulation of Hepatobiliary Transporters During Liver Injury
Aleksunes, L. M., Ghanem, C. I., & Manautou, J. E. (2025) · Elsevier eBooks · doi:10.1016/b978-0-323-95488-4.00268-0
Liu, E., Weng, Z., Ji, X. Y., Dai, Z., Zhu, J., Lu, L.-F., & Jiang, Z. (2025) · SSRN Electronic Journal · doi:10.2139/ssrn.5374585
- Authors
- Geier, A., Dietrich, C. G., Grote, T., Beuers, U., Prüfer, T., Fraunberger, P., Matern, S., Gartung, C., Gerbes, A. L., & Bilzer, M.
- Affiliations
- RWTH Aachen University (DE)
- Ludwig-Maximilians-Universität München (DE)
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2005-12
- Volume
- 43
- Issue
- 6
- Pages
- 1021-1030
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W2047410156
- Cited by
- 66
- References
- 58
- Citations by year
- 2025: 6 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 1 · 2018: 2 · 2017: 4 · 2016: 2 · 2015: 6 · 2014: 4 · 2013: 5 · 2012: 3
- FWCI
- 1.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- organic anion transporters, OATP2, MRP2, MRP4, HNF-3beta, bile salt secretion, bile flow, glutathione metabolism, non-alcoholic fatty liver disease, Zucker fatty rats, hepatobiliary transporters, hepatic steatosis
- MeSH terms
- Animals, Bile, Disease Models, Animal, Fatty Liver, Glutathione, Male, Obesity, Rats, Zucker, ATP-Binding Cassette Transporters, Organic Anion Transporters, Rats
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