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7. Bile formation in long-term ex situ perfused livers

Author

Eshmuminov, Dilmurodjon, Schuler, Martin J., Becker, Dustin, Bautista Borrego, Lucia, Mueller, Matteo, Hagedorn, Catherine, Häusler, Stephanie, Steiger, Julia, Tibbitt, Mark W., Dutkowski, Philipp, Rudolf von Rohr, Philipp, Stieger, Bruno, Hefti, Max, and Clavien, Pierre-Alain

Published
2021
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20. Association Between Gadoxetic Acid-Enhanced Magnetic Resonance Imaging, Organic Anion Transporters, and Farnesoid X Receptor in Benign Focal Liver Lesions

Author

van Rosmalen, Belle V., Visentin, Michele, Furumaya, Alicia, van Delden, Otto M., Kazemier, Geert, van Gulik, Thomas M., Verheij, Joanne, and Stieger, Bruno

Abstract

The organic anion uptake and efflux transporters [organic anion-transporting polypeptide (OATP)1B1, OATP1B3 and multidrug resistance-associated protein (MRP)2 and MRP3] that mediate the transport of the hepatobiliary-specific contrast agent gadoxetate (Gd-EOB-DTPA) are direct or indirect targets of the farnesoid X receptor (FXR), a key regulator of bile acid and lipid homeostasis. In benign liver tumors, FXR expression and activation is not yet characterized. We investigated the expression and activation of FXR and its targets in hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH) and their correlation with Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI). Gd-EOB-DTPA MRI patterns were assessed by an expert radiologist. The intensity of the lesions on the hepatobiliary phase was correlated to mRNA expression levels of OATP1B1, OATP1B3, MRP2, MRP3, FXR, and small heterodimer partner (SHP) in fresh surgical specimens of patients with FNH or HCA subtypes. Normal and tumor sample pairs of 43 HCA and 14 FNH were included. All FNH (14/14) were hyperintense. Of the 34 HCA with available Gd-EOB-DTPA-enhanced MRI, 6 were hyperintense and 28 HCA were hypointense. OATP1B3 was downregulated in the hypointense tumors compared with normal surrounding liver tissue (2.77±3.59 vs. 12.9±15.6, P< 0.001). A significant positive correlation between FXR expression and activation and OATP1B3 expression level was found in the HCA cohort. SHP showed a trend toward downregulation in hypointense HCA. In conclusion, this study suggests that the MRI relative signal in HCA may reflect expression level and/or activity of SHP and FXR. Moreover, our data confirms the pivotal role of OATP1B3 in Gd-EOB-DTPA uptake in HCA.SIGNIFICANCE STATEMENTFXR represents a valuable target for the treatment of liver disease and metabolic syndrome. Currently, two molecules, ursodeoxycholate and obeticholate, are approved for the treatment of primary biliary cirrhosis and cholestasis, with several compounds in clinical trials for the treatment of metabolic dysfunction-associated fatty liver disease. Because FXR expression and activation is associated with gadoxetate accumulation in HCA, an atypical gadoxetate-enhanced MRI pattern might arise in patients under FXR-targeted therapy, thereby complicating the differential diagnosis.

Published
2024
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33. Cloning and characterization of a novel functional organic anion transporting polypeptide 3A1 isoform highly expressed in the human brain and testis

Author

Bakos, Éva, primary, Német, Orsolya, additional, Kucsma, Nóra, additional, Tőkési, Natália, additional, Stieger, Bruno, additional, Rushing, Elisabeth, additional, Tőkés, Anna-Mária, additional, Kele, Péter, additional, Tusnády, Gábor E., additional, and Özvegy-Laczka, Csilla, additional

Published
2022
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38. Bioorthogonal site-selective conjugation of fluorescent dyes to antibodies: method and potential applications

Author

Grossenbacher, Philipp; https://orcid.org/0000-0001-8266-6882, Essers, Maria C, Moser, Joël, Singer, Simon A, Häusler, Stephanie, Stieger, Bruno; https://orcid.org/0000-0002-7190-5785, Rougier, Jean-Sébastien, Lochner, Martin; https://orcid.org/0000-0003-4930-1886, Grossenbacher, Philipp; https://orcid.org/0000-0001-8266-6882, Essers, Maria C, Moser, Joël, Singer, Simon A, Häusler, Stephanie, Stieger, Bruno; https://orcid.org/0000-0002-7190-5785, Rougier, Jean-Sébastien, and Lochner, Martin; https://orcid.org/0000-0003-4930-1886

Abstract

Antibodies are immensely useful tools for biochemical research and have found application in numerous protein detection and purification methods. Moreover, monoclonal antibodies are increasingly utilised as therapeutics or, conjugated to active pharmaceutical ingredients, in targeted chemotherapy. Several reagents and protocols are reported to synthesise fluorescent antibodies for protein target detection and immunofluorescence applications. However, most of these protocols lead to non-selective conjugation, over-labelling or in the worst case antigen binding site modification. Here, we have used the antibody disulphide cleavage and re-bridging strategy to introduce bright fluorescent dyes without loss of the antibody function. The resulting fluorescent IgG1 type antibodies were shown to be effective imaging tools in western blot and direct immunofluorescence experiments.

Published
2022

39. Cloning and characterization of a novel functional organic anion transporting polypeptide 3A1 isoform highly expressed in the human brain and testis

Author

Bakos, Éva, Német, Orsolya, Kucsma, Nóra, Tőkési, Natália, Stieger, Bruno, Rushing, Elisabeth, Tőkés, Anna-Mária, Kele, Péter, Tusnády, Gábor E, Özvegy-Laczka, Csilla, Bakos, Éva, Német, Orsolya, Kucsma, Nóra, Tőkési, Natália, Stieger, Bruno, Rushing, Elisabeth, Tőkés, Anna-Mária, Kele, Péter, Tusnády, Gábor E, and Özvegy-Laczka, Csilla

Abstract

Organic anion transporting polypeptide 3A1 (OATP3A1, encoded by the SLCO3A1 gene) is a prostaglandin, oligopeptide, and steroid/thyroid hormone transporter with wide tissue distribution, expressed, e.g., in the human brain and testis. Although the physiological importance of OATP3A1 has not yet been clarified, based on its expression pattern, substrate recognition, and evolutionary conservation, OATP3A1 is a potential pharmacological target. Previously, two isoforms of OATP3A1, termed as V1 and V2, have been characterized. Here, we describe the cloning and functional characterization of a third isoform, OATP3A1_V3. The mRNA of isoform V3 is formed by alternative splicing and results in an OATP3A1 protein with an altered C-terminus compared to isoforms V1 and V2. Based on quantitative PCR, we demonstrate the widespread expression of SLCO3A1_V3 mRNA in human organs, with the highest expression in the brain and testis. By generation of an isoform V3-specific antibody and immunostaining, we show that the encoded protein is expressed in the human choroid plexus, neurons, and both germ and Sertoli cells of the testis. Moreover, we demonstrate that in contrast to isoform V1, OATP3A1_V3 localizes to the apical membrane of polarized MDCKII cells. Using HEK-293 cells engineered to overexpress OATP3A1_V3, we verify the protein’s functionality and identify dehydroepiandrosterone sulfate as a novel OATP3A1 substrate. Based on their distinct expression patterns but overlapping functions, OATP3A1 isoforms may contribute to transcellular (neuro)steroid transport in the central nervous system.

Published
2022

40. Glucose Transporter 9 (GLUT9) Plays an Important Role in the Placental Uric Acid Transport System

Author

Lüscher, Benjamin P, Albrecht, Christiane; https://orcid.org/0000-0002-7846-6930, Stieger, Bruno, Surbek, Daniel V, Baumann, Marc U, Lüscher, Benjamin P, Albrecht, Christiane; https://orcid.org/0000-0002-7846-6930, Stieger, Bruno, Surbek, Daniel V, and Baumann, Marc U

Abstract

Background: Hyperuricemia is a common laboratory finding in pregnant women compromised by preeclampsia. A growing body of evidence suggests that uric acid is involved in the pathogenesis of preeclampsia. Glucose transporter 9 (GLUT9) is a high-capacity uric acid transporter. The aim of this study was to investigate the placental uric acid transport system, and to identify the (sub-) cellular localization of GLUT9. Methods: Specific antibodies against GLUT9a and GLUT9b isoforms were raised, and human villous (placental) tissue was immunohistochemically stained. A systemic GLUT9 knockout (G9KO) mouse model was used to assess the placental uric acid transport capacity by measurements of uric acid serum levels in the fetal and maternal circulation. Results: GLUT9a and GLUT9b co-localized with the villous (apical) membrane, but not with the basal membrane, of the syncytiotrophoblast. Fetal and maternal uric acid serum levels were closely correlated. G9KO fetuses showed substantially higher uric acid serum concentrations than their mothers. Conclusions: These findings demonstrate that the placenta efficiently maintains uric acid homeostasis, and that GLUT9 plays a key role in the placental uric acid transport system, at least in this murine model. Further studies investigating the role of the placental uric acid transport system in preeclampsia are eagerly needed.

Published
2022

46. Bioorthogonal site-selective conjugation of fluorescent dyes to antibodies: method and potential applications

Author

Grossenbacher, Philipp, Essers, Maria C, Moser, Joël, Singer, Simon A, Häusler, Stephanie, Stieger, Bruno, Rougier, Jean-Sébastien, Lochner, Martin, and University of Zurich

Subjects
10199 Clinic for Clinical Pharmacology and Toxicology, General Chemical Engineering, 540 Chemistry, 570 Life sciences, biology, 610 Medicine & health, General Chemistry
Abstract

Antibodies are immensely useful tools for biochemical research and have found application in numerous protein detection and purification methods. Moreover, monoclonal antibodies are increasingly utilised as therapeutics or, conjugated to active pharmaceutical ingredients, in targeted chemotherapy. Several reagents and protocols are reported to synthesise fluorescent antibodies for protein target detection and immunofluorescence applications. However, most of these protocols lead to non-selective conjugation, over-labelling or in the worst case antigen binding site modification. Here, we have used the antibody disulphide cleavage and re-bridging strategy to introduce bright fluorescent dyes without loss of the antibody function. The resulting fluorescent IgG1 type antibodies were shown to be effective imaging tools in western blot and direct immunofluorescence experiments.

Published
2022
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