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Impact of the NADPH pool in the endoplasmic reticulum on metabolic and hormonal regulation

English title Impact of the NADPH pool in the endoplasmic reticulum on metabolic and hormonal regulation
Applicant Odermatt Alexander
Number 179400
Funding scheme Project funding (Div. I-III)
Research institution Abteilung Molekular- und Systemtoxikologie Departement Pharmazeutische Wissenschaften Universität Basel
Institution of higher education University of Basel - BS
Main discipline Biochemistry
Start/End 01.05.2018 - 30.04.2022
Approved amount 793'892.00
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All Disciplines (2)

Discipline
Biochemistry
Endocrinology

Keywords (9)

endoplasmic reticulum; unfolded protein response; NADPH; hexose-6-phosphate dehydrogenase; redox; oxysterol; bile acid; 11beta-hydroxysteroid dehydrogenase; glucocorticoid

Lay Summary (German)

Lead
Das Endoplasmatischen Retikulum (ER) spielt eine zentrale Rolle in der Proteinfaltung und in metabolischen Prozessen. Eine gestörte Funktion des ER ist mit Krankheiten wie Krebs, kardiovaskulären Erkrankungen und chronischen Entzündungserkrankungen assoziiert. Die Rolle von NADPH im ER und dessen Einfluss auf Oxydationsprozesse und metabolische Reaktionen ist noch ungenügend untersucht. Das Projekt untersucht diese Reaktionen hinsichtlich Aufklärung von physiologischen und pathologischen Prozessen.
Lay summary

Das Projekt untersucht Mechanismen in der Bildung und im Verbrauch des Reduktionsäquivalents NADPH im ER. Die Relevanz von NADPH im ER für physiologische Funktionen wie Kalziumhaushalt, Proteinfaltung und dem Metabolismus von Steroiden, Oxysterole und Gallensäuren wird studiert. Zudem wird nach neuen Modulatoren des ER NADPH Haushalts gesucht. Metabolische Effekte und Effekte auf ER-Stress Signalwege werden in Nieren- und Leberzellen untersucht. Im Weiteren wird der Einfluss von ER NADPH auf den Fettsäuren Metabolismus und auf Zellwachstum untersucht.

Für die Experimente werden Enzym Präparationen, Zellmodelle sowie transgene Mäuse eingesetzt. Zudem wird versucht eine Methode zum Nachweis von Protein-Protein Interaktionen im ER zu etablieren.

Die zu erwartenden Resultate sollen die Rolle des NADPH im ER aufklären und eine Verbindung zwischen zellulärem Energiehaushalt und hormoneller Regulation aufzeigen. Störungen im ER NADPH, die zu ER-Stress und oxidativem Stress führen, können zu Krankheiten beitragen. Die zu erwartenden Resultate sollen diese Mechanismen besser verstehen helfen und die zukünftige Entwicklung von therapeutischen Interventionen unterstützen.   

Direct link to Lay Summary Last update: 24.04.2018

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
AKR1D1 knockout mice develop a sex-dependent metabolic phenotype
Gathercole Laura L, Nikolaou Nikolaos, Harris Shelley E, Arvaniti Anastasia, Poolman Toryn M, Hazlehurst Jonathan M, Kratschmar Denise V, Todorčević Marijana, Moolla Ahmad, Dempster Niall, Pink Ryan C, Saikali Michael F, Bentley Liz, Penning Trevor M, Ohlsson Claes, Cummins Carolyn L, Poutanen Matti, Odermatt Alex, Cox Roger D, Tomlinson Jeremy W (2022), AKR1D1 knockout mice develop a sex-dependent metabolic phenotype, in Journal of Endocrinology, 253(3), 97-113.
Albendazole reduces hepatic inflammation and endoplasmic reticulum-stress in a mouse model of chronic Echinococcus multilocularis infection
Weingartner Michael, Stücheli Simon, Jebbawi Fadi, Gottstein Bruno, Beldi Guido, Lundström-Stadelmann Britta, Wang Junhua, Odermatt Alex (2022), Albendazole reduces hepatic inflammation and endoplasmic reticulum-stress in a mouse model of chronic Echinococcus multilocularis infection, in PLOS Neglected Tropical Diseases, 16(1), e0009192-e0009192.
Modulation of 11β-hydroxysteroid dehydrogenase functions by the cloud of endogenous metabolites in a local microenvironment: The glycyrrhetinic acid-like factor (GALF) hypothesis
Morris David J., Brem Andrew S., Odermatt Alex (2021), Modulation of 11β-hydroxysteroid dehydrogenase functions by the cloud of endogenous metabolites in a local microenvironment: The glycyrrhetinic acid-like factor (GALF) hypothesis, in The Journal of Steroid Biochemistry and Molecular Biology, 214, 105988-105988.
The ratio of ursodeoxycholyltaurine to 7‐oxolithocholyltaurine serves as a biomarker of decreased 11β‐hydroxysteroid dehydrogenase 1 activity in mouse
Weingartner Michael, Stücheli Simon, Kratschmar Denise V., Birk Julia, Klusonova Petra, Chapman Karen E., Lavery Gareth G., Odermatt Alex (2021), The ratio of ursodeoxycholyltaurine to 7‐oxolithocholyltaurine serves as a biomarker of decreased 11β‐hydroxysteroid dehydrogenase 1 activity in mouse, in British Journal of Pharmacology, 178(16), 3309-3326.
Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice
Gómez Cristina, Jebbawi Fadi, Weingartner Michael, Wang Junhua, Stücheli Simon, Stieger Bruno, Gottstein Bruno, Beldi Guido, Lundström-Stadelmann Britta, Odermatt Alex (2021), Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice, in Metabolites, 11(7), 442-442.
Loss of Claudin-3 Impairs Hepatic Metabolism, Biliary Barrier Function, and Cell Proliferation in the Murine Liver
Baier Felix Alexander, Sánchez-Taltavull Daniel, Yarahmadov Tural, Castellà Cristina Gómez, Jebbawi Fadi, Keogh Adrian, Tombolini Riccardo, Odriozola Adolfo, Dias Mariana Castro, Deutsch Urban, Furuse Mikio, Engelhardt Britta, Zuber Benoît, Odermatt Alex, Candinas Daniel, Stroka Deborah (2021), Loss of Claudin-3 Impairs Hepatic Metabolism, Biliary Barrier Function, and Cell Proliferation in the Murine Liver, in Cellular and Molecular Gastroenterology and Hepatology, 12(2), 745-767.
Monitoring Changes in the Oxidizing Milieu in the Endoplasmic Reticulum of Mammalian Cells Using HyPerER
Birk Julia, Lizak Beata, Appenzeller-Herzog Christian, Odermatt Alex (2021), Monitoring Changes in the Oxidizing Milieu in the Endoplasmic Reticulum of Mammalian Cells Using HyPerER, in BIO-PROTOCOL, 11(13), e4076-e4076.
Inhibition of IL-1beta improves Glycaemia in a Mouse Model for Gestational Diabetes
Schulze Friederike, Wehner Josua, Kratschmar Denise V., Makshana Valmir, Meier Daniel T., Häuselmann Stéphanie P., Dalmas Elise, Thienel Constanze, Dror Erez, Wiedemann Sophia J., Traub Shuyang, Nordmann Thierry M., Rachid Leila, De Baat Axel, Rohm Theresa V., Zhao Cheng, Odermatt Alex, Böni-Schnetzler Marianne, Donath Marc Y. (2020), Inhibition of IL-1beta improves Glycaemia in a Mouse Model for Gestational Diabetes, in Scientific Reports, 10(1), 3035-3035.
Development and Validation of a Highly Sensitive LC-MS/MS Method for the Analysis of Bile Acids in Serum, Plasma, and Liver Tissue Samples
Gómez Cristina, Stücheli Simon, Kratschmar Denise V., Bouitbir Jamal, Odermatt Alex (2020), Development and Validation of a Highly Sensitive LC-MS/MS Method for the Analysis of Bile Acids in Serum, Plasma, and Liver Tissue Samples, in Metabolites, 10(7), 282-282.
Impact of 17β-HSD12, the 3-ketoacyl-CoA reductase of long-chain fatty acid synthesis, on breast cancer cell proliferation and migration
Tsachaki Maria, Strauss Pirmin, Dunkel Anja, Navrátilová Hana, Mladenovic Natasa, Odermatt Alex (2020), Impact of 17β-HSD12, the 3-ketoacyl-CoA reductase of long-chain fatty acid synthesis, on breast cancer cell proliferation and migration, in Cellular and Molecular Life Sciences, 77(6), 1153-1175.
Treatment of Primary Aldosteronism With mTORC1 Inhibitors
Trinh Beckey, Hepprich Matthias, Betz Matthias J, Burkard Thilo, Cavelti-Weder Claudia, Seelig Eleonora, Meienberg Fabian, Kratschmar Denise V, Beuschlein Felix, Reincke Martin, Odermatt Alex, Hall Michael N, Donath Marc Y, Swierczynska Marta M (2019), Treatment of Primary Aldosteronism With mTORC1 Inhibitors, in The Journal of Clinical Endocrinology & Metabolism, 104(10), 4703-4714.
Enzymatic interconversion of the oxysterols 7β,25-dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2
Beck Katharina R., Kanagaratnam Sharavan, Kratschmar Denise V., Birk Julia, Yamaguchi Hideaki, Sailer Andreas W., Seuwen Klaus, Odermatt Alex (2019), Enzymatic interconversion of the oxysterols 7β,25-dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2, in The Journal of Steroid Biochemistry and Molecular Biology, 190, 19-28.
Profiling withanolide A for therapeutic targets in neurodegenerative diseases
Crane Erika A., Heydenreuter Wolfgang, Beck Katharina R., Strajhar Petra, Vomacka Jan, Smiesko Martin, Mons Elma, Barth Lydia, Neuburger Markus, Vedani Angelo, Odermatt Alex, Sieber Stephan A., Gademann Karl (2019), Profiling withanolide A for therapeutic targets in neurodegenerative diseases, in Bioorganic & Medicinal Chemistry, 27(12), 2508-2520.
Removal of batch effects using stratified subsampling of metabolomic data for in vitro endocrine disruptors screening
Boccard Julien, Tonoli David, Strajhar Petra, Jeanneret Fabienne, Odermatt Alex, Rudaz Serge (2019), Removal of batch effects using stratified subsampling of metabolomic data for in vitro endocrine disruptors screening, in Talanta, 195, 77-86.
Effects of lisdexamfetamine on plasma steroid concentrations compared with d-amphetamine in healthy subjects: A randomized, double-blind, placebo-controlled study
Strajhar Petra, Vizeli Patrick, Patt Melanie, Dolder Patrick C., Kratschmar Denise V., Liechti Matthias E., Odermatt Alex (2019), Effects of lisdexamfetamine on plasma steroid concentrations compared with d-amphetamine in healthy subjects: A randomized, double-blind, placebo-controlled study, in The Journal of Steroid Biochemistry and Molecular Biology, 186, 212-225.
11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ
Beck Katharina R., Inderbinen Silvia G., Kanagaratnam Sharavan, Kratschmar Denise V., Jetten Anton M., Yamaguchi Hideaki, Odermatt Alex (2019), 11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ, in Journal of Lipid Research, 60(9), 1535-1546.
Subcellular localization and membrane topology of 17β-hydroxysteroid dehydrogenases
Tsachaki Maria, Odermatt Alex (2019), Subcellular localization and membrane topology of 17β-hydroxysteroid dehydrogenases, in Molecular and Cellular Endocrinology, 98-106.
Absence of hexose-6-phosphate dehydrogenase results in reduced overall glucose consumption but does not prevent 11β-hydroxysteroid dehydrogenase-1-dependent glucocorticoid activation
Marbet Philippe, Klusonova Petra, Birk Julia, Kratschmar Denise V., Odermatt Alex (2018), Absence of hexose-6-phosphate dehydrogenase results in reduced overall glucose consumption but does not prevent 11β-hydroxysteroid dehydrogenase-1-dependent glucocorticoid activation, in The FEBS Journal, 285(21), 3993-4004.
Design, synthesis, and biological evaluation of novel selective peptide inhibitors of 11β-hydroxysteroid dehydrogenase 1
Boudon Stephanie, Heidl Marc, Vuorinen Anna, Wandeler Eliane, Campiche Remo, Odermatt Alex, Jackson Eileen (2018), Design, synthesis, and biological evaluation of novel selective peptide inhibitors of 11β-hydroxysteroid dehydrogenase 1, in Bioorganic & Medicinal Chemistry, 26(18), 5128-5139.

Datasets

Data_Figure 7_11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

Author Beck, Katharina R.; Inderbinen, Silvia G.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Jetten, Anton M.; Yamaguchi, Hideaki; Odermatt, Alex
Publication date 01.09.2019
Persistent Identifier (PID) doi:10.1194/jlr.M092908
Repository Zenodo


Data_text section 3.1_Enzymatic interconversion of the oxysterols 7β,25 dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2

Author Beck, Katharina R.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Birk, Julia; Yamaguchi, Hideaki; Sailer, Andreas W.; Seuwen, Klaus; Odermatt, Alex
Publication date 01.06.2019
Persistent Identifier (PID) doi:10.1016/j.jsbmb.2019.03.011
Repository Zenodo


Data_Figure 8_11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

Author Beck, Katharina R.; Inderbinen, Silvia G.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Jetten, Anton M.; Yamaguchi, Hideaki; Odermatt, Alex
Publication date 01.09.2019
Persistent Identifier (PID) doi:10.1194/jlr.M092908
Repository Zenodo


Data_supplemental figure 5_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_supplemental figure 7_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_supplemental figure 2_Enzymatic interconversion of the oxysterols 7β,25 dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2

Author Beck, Katharina R.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Birk, Julia; Yamaguchi, Hideaki; Sailer, Andreas W.; Seuwen, Klaus; Odermatt, Alex
Publication date 01.06.2019
Persistent Identifier (PID) doi:10.1016/j.jsbmb.2019.03.011
Repository Zenodo


Data_Figure 5_Enzymatic interconversion of the oxysterols 7β,25 dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2

Author Beck, Katharina R.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Birk, Julia; Yamaguchi, Hideaki; Sailer, Andreas W.; Seuwen, Klaus; Odermatt, Alex
Publication date 01.06.2019
Persistent Identifier (PID) doi:10.1016/j.jsbmb.2019.03.011
Repository Zenodo


Data_Figure 3_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_Figure 2_11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

Author Beck, Katharina R.; Inderbinen, Silvia G.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Jetten, Anton M.; Yamaguchi, Hideaki; Odermatt, Alex
Publication date 01.09.2019
Persistent Identifier (PID) doi:10.1194/jlr.M092908
Repository Zenodo


Data_supplemental figure 1_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_Figure 5_11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

Author Beck, Katharina R.; Inderbinen, Silvia G.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Jetten, Anton M.; Yamaguchi, Hideaki; Odermatt, Alex
Publication date 01.09.2019
Persistent Identifier (PID) doi:10.1194/jlr.M092908
Repository Zenodo


Data_Figure 1_11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

Author Beck, Katharina R.; Inderbinen, Silvia G.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Jetten, Anton M.; Yamaguchi, Hideaki; Odermatt, Alex
Publication date 01.09.2019
Persistent Identifier (PID) doi:10.1194/jlr.M092908
Repository Zenodo


Data_Figure 3_Enzymatic interconversion of the oxysterols 7β,25 dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2

Author Beck, Katharina R.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Birk, Julia; Yamaguchi, Hideaki; Sailer, Andreas W.; Seuwen, Klaus; Odermatt, Alex
Publication date 01.06.2019
Persistent Identifier (PID) doi:10.1016/j.jsbmb.2019.03.011
Repository Zenodo


Data_text section_ 11βHSD1_11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

Author Beck, Katharina R.; Inderbinen, Silvia G.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Jetten, Anton M.; Yamaguchi, Hideaki; Odermatt, Alex
Publication date 01.09.2019
Persistent Identifier (PID) doi:10.1194/jlr.M092908
Repository Zenodo


Data_Figure 6_Enzymatic interconversion of the oxysterols 7β,25 dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2

Author Beck, Katharina R.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Birk, Julia; Yamaguchi, Hideaki; Sailer, Andreas W.; Seuwen, Klaus; Odermatt, Alex
Publication date 01.06.2019
Persistent Identifier (PID) doi:10.1016/j.jsbmb.2019.03.011
Repository Zenodo


Data_supplemental Figure 4_11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

Author Beck, Katharina R.; Inderbinen, Silvia G.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Jetten, Anton M.; Yamaguchi, Hideaki; Odermatt, Alex
Publication date 01.09.2019
Persistent Identifier (PID) doi:10.1194/jlr.M092908
Repository Zenodo


Data_Figure 1_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_supplemental figure 8_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_Figure 7_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_Figure 6_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_supplemental Figure 1_11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

Author Beck, Katharina R.; Inderbinen, Silvia G.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Jetten, Anton M.; Yamaguchi, Hideaki; Odermatt, Alex
Publication date 01.09.2019
Persistent Identifier (PID) doi:10.1194/jlr.M092908
Repository Zenodo


Data_Figure 4_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_Figure 5_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_text section 11βHSD2_11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

Author Beck, Katharina R.; Inderbinen, Silvia G.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Jetten, Anton M.; Yamaguchi, Hideaki; Odermatt, Alex
Publication date 01.09.2019
Persistent Identifier (PID) doi:10.1194/jlr.M092908
Repository Zenodo


Data_Figure 3 _11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

Author Beck, Katharina R.; Inderbinen, Silvia G.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Jetten, Anton M.; Yamaguchi, Hideaki; Odermatt, Alex
Publication date 01.09.2019
Persistent Identifier (PID) doi:10.1194/jlr.M092908
Repository Zenodo


Data_supplemental table 1_Enzymatic interconversion of the oxysterols 7β,25 dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2

Author Beck, Katharina R.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Birk, Julia; Yamaguchi, Hideaki; Sailer, Andreas W.; Seuwen, Klaus; Odermatt, Alex
Publication date 01.06.2019
Persistent Identifier (PID) doi:10.1016/j.jsbmb.2019.03.011
Repository Zenodo


Data_supplemental figure 10_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_text section 3.3_Enzymatic interconversion of the oxysterols 7β,25 dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2

Author Beck, Katharina R.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Birk, Julia; Yamaguchi, Hideaki; Sailer, Andreas W.; Seuwen, Klaus; Odermatt, Alex
Publication date 01.06.2019
Persistent Identifier (PID) doi:10.1016/j.jsbmb.2019.03.011
Repository Zenodo


Data_Figure 2_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_Figure 6_11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

Author Beck, Katharina R.; Inderbinen, Silvia G.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Jetten, Anton M.; Yamaguchi, Hideaki; Odermatt, Alex
Publication date 01.09.2019
Persistent Identifier (PID) doi:10.1194/jlr.M092908
Repository Zenodo


Data_Figure 2_Enzymatic interconversion of the oxysterols 7β,25 dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2

Author Beck, Katharina R.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Birk, Julia; Yamaguchi, Hideaki; Sailer, Andreas W.; Seuwen, Klaus; Odermatt, Alex
Publication date 01.06.2019
Persistent Identifier (PID) doi:10.1016/j.jsbmb.2019.03.011
Repository Zenodo


Data_supplemental Figure 2_11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

Author Beck, Katharina R.; Inderbinen, Silvia G.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Jetten, Anton M.; Yamaguchi, Hideaki; Odermatt, Alex
Publication date 01.09.2019
Persistent Identifier (PID) doi:10.1194/jlr.M092908
Repository Zenodo


Data_supplemental figure 3_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_supplemental figure 4_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_supplemental figure 9_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_supplemental figure 2_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_supplemental figure 1_Enzymatic interconversion of the oxysterols 7β,25 dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2

Author Beck, Katharina R.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Birk, Julia; Yamaguchi, Hideaki; Sailer, Andreas W.; Seuwen, Klaus; Odermatt, Alex
Publication date 01.06.2019
Persistent Identifier (PID) doi:10.1016/j.jsbmb.2019.03.011
Repository Zenodo


Data_Figure 4_Enzymatic interconversion of the oxysterols 7β,25 dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2

Author Beck, Katharina R.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Birk, Julia; Yamaguchi, Hideaki; Sailer, Andreas W.; Seuwen, Klaus; Odermatt, Alex
Publication date 01.06.2019
Persistent Identifier (PID) doi:10.1016/j.jsbmb.2019.03.011
Repository Zenodo


Data_Figure 8_Enzymatic interconversion of the oxysterols 7β,25 dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2

Author Beck, Katharina R.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Birk, Julia; Yamaguchi, Hideaki; Sailer, Andreas W.; Seuwen, Klaus; Odermatt, Alex
Publication date 01.06.2019
Persistent Identifier (PID) doi:10.1016/j.jsbmb.2019.03.011
Repository Zenodo


Data_supplemental figure 6_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_supplemental Figure 3_11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

Author Beck, Katharina R.; Inderbinen, Silvia G.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Jetten, Anton M.; Yamaguchi, Hideaki; Odermatt, Alex
Publication date 01.09.2019
Persistent Identifier (PID) doi:10.1194/jlr.M092908
Repository Zenodo


Data_Figure 8_Impact of 17β‑HSD12, the 3‑ketoacyl‑CoA reductase of long‑chain fatty acid synthesis, on breast cancer cell proliferation and migration

Author Tsachaki, Maria; Strauss, Pirmin; Dunkel, Anja; Navrátilová, Hana; Mladenovic, Natasa; Odermatt, Alex
Publication date 13.03.2020
Persistent Identifier (PID) doi: 10.1007/s00018-019-03227-w
Repository Zenodo


Data_Figure 9_11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

Author Beck, Katharina R.; Inderbinen, Silvia G.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Jetten, Anton M.; Yamaguchi, Hideaki; Odermatt, Alex
Publication date 01.09.2019
Persistent Identifier (PID) doi:10.1194/jlr.M092908
Repository Zenodo


Data_Figure 7_Enzymatic interconversion of the oxysterols 7β,25 dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2

Author Beck, Katharina R.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Birk, Julia; Yamaguchi, Hideaki; Sailer, Andreas W.; Seuwen, Klaus; Odermatt, Alex
Publication date 01.06.2019
Persistent Identifier (PID) doi:10.1016/j.jsbmb.2019.03.011
Repository Zenodo


Data_supplemental figure 3_Enzymatic interconversion of the oxysterols 7β,25 dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2

Author Beck, Katharina R.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Birk, Julia; Yamaguchi, Hideaki; Sailer, Andreas W.; Seuwen, Klaus; Odermatt, Alex
Publication date 01.06.2019
Persistent Identifier (PID) 10.1016/j.jsbmb.2019.03.011
Repository Zenodo


Data_Figure 1_Enzymatic interconversion of the oxysterols 7β,25 dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2

Author Beck, Katharina R.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Birk, Julia; Yamaguchi, Hideaki; Sailer, Andreas W.; Seuwen, Klaus; Odermatt, Alex
Publication date 01.06.2019
Persistent Identifier (PID) doi:10.1016/j.jsbmb.2019.03.011
Repository Zenodo


Data_Figure 4_11β-Hydroxysteroid dehydrogenases control access of 7β,27-dihydroxycholesterol to retinoid-related orphan receptor γ

Author Beck, Katharina R.; Inderbinen, Silvia G.; Kanagaratnam, Sharavan; Kratschmar, Denise V.; Jetten, Anton M.; Yamaguchi, Hideaki; Odermatt, Alex
Publication date 01.09.2019
Persistent Identifier (PID) doi:10.1194/jlr.M092908
Repository Zenodo


Data_Figure 1_Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice

Author Gómez, Cristina; Jebbawi, Fadi; Weingartner, Michael; Wang, Junhua; Stücheli, Simon; Stieger, Bruno; Gottstein, Bruno; Beldi, Guido; Lundström-Stadelmann, Britta; Odermatt, Alex
Publication date 06.07.2021
Persistent Identifier (PID) 10.5281/zenodo.5112858
Repository Zenodo


Data_Figure 2_Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice

Author Gómez, Cristina; Jebbawi, Fadi; Weingartner, Michael; Wang, Junhua; Stücheli, Simon; Stieger, Bruno; Gottstein, Bruno; Beldi, Guido; Lundström-Stadelmann, Britta; Odermatt, Alex
Publication date 06.07.2021
Persistent Identifier (PID) 10.5281/zenodo.5112922
Repository Zenodo
Abstract
infection. ABZ itself had no effect on the bile acid profiles and the expression of relevant enzymes and transporters. Further research is needed to uncover the exact mechanism of the AE-induced changes in bile acid homeostasis and to test whether serum bile acids and ratios thereof can serve as biomarkers of AE and for monitoring therapeutic efficacy.

Data_Figure 3_Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice

Author Gómez, Cristina; Jebbawi, Fadi; Weingartner, Michael; Wang, Junhua; Stücheli, Simon; Stieger, Bruno; Gottstein, Bruno; Beldi, Guido; Lundström-Stadelmann, Britta; Odermatt, Alex
Publication date 06.07.2021
Persistent Identifier (PID) 10.5281/zenodo.5112937
Repository Zenodo
Abstract
infection. ABZ itself had no effect on the bile acid profiles and the expression of relevant enzymes and transporters. Further research is needed to uncover the exact mechanism of the AE-induced changes in bile acid homeostasis and to test whether serum bile acids and ratios thereof can serve as biomarkers of AE and for monitoring therapeutic efficacy.

Data_Figure 4_Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice

Author Gómez, Cristina; Jebbawi, Fadi; Weingartner, Michael; Wang, Junhua; Stücheli, Simon; Stieger, Bruno; Gottstein, Bruno; Beldi, Guido; Lundström-Stadelmann, Britta; Odermatt, Alex
Publication date 06.07.2021
Persistent Identifier (PID) 10.5281/zenodo.5112955
Repository Zenodo
Abstract
infection. ABZ itself had no effect on the bile acid profiles and the expression of relevant enzymes and transporters. Further research is needed to uncover the exact mechanism of the AE-induced changes in bile acid homeostasis and to test whether serum bile acids and ratios thereof can serve as biomarkers of AE and for monitoring therapeutic efficacy.

Data_Figure 5_Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Miceazole in Mice

Author Gómez, Cristina; Jebbawi, Fadi; Weingartner, Michael; Wang, Junhua; Stücheli, Simon; Stieger, Bruno; Gottstein, Bruno; Beldi, Guido; Lundström-Stadelmann, Britta; Odermatt, Alex
Publication date 06.07.2021
Persistent Identifier (PID) 10.5281/zenodo.5113005
Repository Zenodo
Abstract
infection. ABZ itself had no effect on the bile acid profiles and the expression of relevant enzymes and transporters. Further research is needed to uncover the exact mechanism of the AE-induced changes in bile acid homeostasis and to test whether serum bile acids and ratios thereof can serve as biomarkers of AE and for monitoring therapeutic efficacy.

Data_Table 1_Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice

Author Gómez, Cristina; Jebbawi, Fadi; Weingartner, Michael; Wang, Junhua; Stücheli, Simon; Stieger, Bruno; Gottstein, Bruno; Beldi, Guido; Lundström-Stadelmann, Britta; Odermatt, Alex
Publication date 06.07.2021
Persistent Identifier (PID) 10.5281/zenodo.5113014
Repository Zenodo
Abstract
infection. ABZ itself had no effect on the bile acid profiles and the expression of relevant enzymes and transporters. Further research is needed to uncover the exact mechanism of the AE-induced changes in bile acid homeostasis and to test whether serum bile acids and ratios thereof can serve as biomarkers of AE and for monitoring therapeutic efficacy.

Data_Table 2_Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice

Author Gómez, Cristina; Jebbawi, Fadi; Weingartner, Michael; Wang, Junhua; Stücheli, Simon; Stieger, Bruno; Gottstein, Bruno; Beldi, Guido; Lundström-Stadelmann, Britta; Odermatt, Alex
Publication date 06.07.2021
Persistent Identifier (PID) 10.5281/zenodo.5113164
Repository Zenodo
Abstract
infection. ABZ itself had no effect on the bile acid profiles and the expression of relevant enzymes and transporters. Further research is needed to uncover the exact mechanism of the AE-induced changes in bile acid homeostasis and to test whether serum bile acids and ratios thereof can serve as biomarkers of AE and for monitoring therapeutic efficacy.

Data_Table 3_Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice

Author Gómez, Cristina; Jebbawi, Fadi; Weingartner, Michael; Wang, Junhua; Stücheli, Simon; Stieger, Bruno; Gottstein, Bruno; Beldi, Guido; Lundström-Stadelmann, Britta; Odermatt, Alex
Publication date 06.07.2021
Persistent Identifier (PID) 10.5281/zenodo.5113188
Repository Zenodo
Abstract
infection. ABZ itself had no effect on the bile acid profiles and the expression of relevant enzymes and transporters. Further research is needed to uncover the exact mechanism of the AE-induced changes in bile acid homeostasis and to test whether serum bile acids and ratios thereof can serve as biomarkers of AE and for monitoring therapeutic efficacy.

Data_Figure S1_Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice

Author Gómez, Cristina; Jebbawi, Fadi; Weingartner, Michael; Wang, Junhua; Stücheli, Simon; Stieger, Bruno; Gottstein, Bruno; Beldi, Guido; Lundström-Stadelmann, Britta; Odermatt, Alex
Publication date 06.07.2021
Persistent Identifier (PID) 10.5281/zenodo.5113216
Repository Zenodo
Abstract
infection. ABZ itself had no effect on the bile acid profiles and the expression of relevant enzymes and transporters. Further research is needed to uncover the exact mechanism of the AE-induced changes in bile acid homeostasis and to test whether serum bile acids and ratios thereof can serve as biomarkers of AE and for monitoring therapeutic efficacy.

Data_Figure S2_Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice

Author Gómez, Cristina; Jebbawi, Fadi; Weingartner, Michael; Wang, Junhua; Stücheli, Simon; Stieger, Bruno; Gottstein, Bruno; Beldi, Guido; Lundström-Stadelmann, Britta; Odermatt, Alex
Publication date 06.07.2021
Persistent Identifier (PID) 10.5281/zenodo.5113231
Repository Zenodo
Abstract
infection. ABZ itself had no effect on the bile acid profiles and the expression of relevant enzymes and transporters. Further research is needed to uncover the exact mechanism of the AE-induced changes in bile acid homeostasis and to test whether serum bile acids and ratios thereof can serve as biomarkers of AE and for monitoring therapeutic efficacy.

Data_Figure S3_Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice

Author Gómez, Cristina; Jebbawi, Fadi; Weingartner, Michael; Wang, Junhua; Stücheli, Simon; Stieger, Bruno; Gottstein, Bruno; Beldi, Guido; Lundström-Stadelmann, Britta; Odermatt, Alex
Publication date 06.07.2021
Persistent Identifier (PID) 10.5281/zenodo.5113250
Repository Zenodo
Abstract
infection. ABZ itself had no effect on the bile acid profiles and the expression of relevant enzymes and transporters. Further research is needed to uncover the exact mechanism of the AE-induced changes in bile acid homeostasis and to test whether serum bile acids and ratios thereof can serve as biomarkers of AE and for monitoring therapeutic efficacy.

Data_Figure S4_Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice

Author Gómez, Cristina; Jebbawi, Fadi; Weingartner, Michael; Wang, Junhua; Stücheli, Simon; Stieger, Bruno; Gottstein, Bruno; Beldi, Guido; Lundström-Stadelmann, Britta; Odermatt, Alex
Publication date 06.07.2021
Persistent Identifier (PID) 10.5281/zenodo.5113259
Repository Zenodo
Abstract
infection. ABZ itself had no effect on the bile acid profiles and the expression of relevant enzymes and transporters. Further research is needed to uncover the exact mechanism of the AE-induced changes in bile acid homeostasis and to test whether serum bile acids and ratios thereof can serve as biomarkers of AE and for monitoring therapeutic efficacy.

Data_Figure S5_Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice

Author Gómez, Cristina; Jebbawi, Fadi; Weingartner, Michael; Wang, Junhua; Stücheli, Simon; Stieger, Bruno; Gottstein, Bruno; Beldi, Guido; Lundström-Stadelmann, Britta; Odermatt, Alex
Publication date 06.07.2021
Persistent Identifier (PID) 10.5281/zenodo.5113270
Repository Zenodo
Abstract
infection. ABZ itself had no effect on the bile acid profiles and the expression of relevant enzymes and transporters. Further research is needed to uncover the exact mechanism of the AE-induced changes in bile acid homeostasis and to test whether serum bile acids and ratios thereof can serve as biomarkers of AE and for monitoring therapeutic efficacy.

Data_Table S1_Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice

Author Gómez, Cristina; Jebbawi, Fadi; Weingartner, Michael; Wang, Junhua; Stücheli, Simon; Stieger, Bruno; Gottstein, Bruno; Beldi, Guido; Lundström-Stadelmann, Britta; Odermatt, Alex
Publication date 06.07.2021
Persistent Identifier (PID) 10.5281/zenodo.5113287
Repository Zenodo
Abstract
infection. ABZ itself had no effect on the bile acid profiles and the expression of relevant enzymes and transporters. Further research is needed to uncover the exact mechanism of the AE-induced changes in bile acid homeostasis and to test whether serum bile acids and ratios thereof can serve as biomarkers of AE and for monitoring therapeutic efficacy.

Data_Table S2_Impact on Bile Acid Concentrations by Alveolar Echinococcosis and Treatment with Albendazole in Mice

Author Gómez, Cristina; Jebbawi, Fadi; Weingartner, Michael; Wang, Junhua; Stücheli, Simon; Stieger, Bruno; Gottstein, Bruno; Beldi, Guido; Lundström-Stadelmann, Britta; Odermatt, Alex
Publication date 06.07.2021
Persistent Identifier (PID) 10.5281/zenodo.5113363
Repository Zenodo
Abstract
infection. ABZ itself had no effect on the bile acid profiles and the expression of relevant enzymes and transporters. Further research is needed to uncover the exact mechanism of the AE-induced changes in bile acid homeostasis and to test whether serum bile acids and ratios thereof can serve as biomarkers of AE and for monitoring therapeutic efficacy.

Data_Fig1_Monitoring Changes in the Oxidizing Milieu in the Endoplasmic Reticulum of Mammalian Cells Using HyPerERER.

Author Birk, Julia; Lizak, Beata; Appenzeller-Herzog, Christian; Odermatt, Alex
Publication date 05.07.2021
Persistent Identifier (PID) 10.5281/zenodo.5082260
Repository Zenodo
Abstract
The production of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress are tightly linked. The generation of ROS can be both the cause and a consequence of ER stress pathways, and an increasing number of human diseases are characterized by tissue atrophy in response to ER stress and oxidative injury. For the assessment of modulators of ER luminal ROS generation and for mechanistic studies, methods to monitor changes in ER reduction-oxidation (redox) states in a time-resolved and organelle-specific manner are needed. This has been greatly facilitated by the development of genetically encoded fluorescent probes, which can be targeted to different subcellular locations by specific amino acid extensions. One of these probes is the yellow fluorescent protein-based redox biosensor, HyPer. Here, we provide a protocol for the time-resolved monitoring of the oxidizing milieu in the ER of adherent mammalian cells using the ratiometric sensor, HyPerER, which is specifically targeted to the ER lumen.

Data_Figure1_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activityroxysteroid dehydrogenase 1 activity in mouse.

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4529381
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_Figure2_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activityroxysteroid dehydrogenase 1 activity in mouse.

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4529417
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_Figure3_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activityroxysteroid dehydrogenase 1 activity in mouse.

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4529506
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_Figure4_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activityroxysteroid dehydrogenase 1 activity in mouse.

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4529977
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_Figure5_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4530109
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_Table1_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity roxysteroid dehydrogenase 1 activity in mouse.

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4530310
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_Table2_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4530461
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_Table3_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4530534
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_Table4_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4530669
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_FigS1_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4536822
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_FigS2_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4536826
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_FigS3_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4536840
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_FigS4_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4536842
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_FigS5_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4536846
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_FigS6_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4536853
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_FigS7_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4536858
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_FigS8_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4536886
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_FigS9_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4536940
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_FigS10_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4536952
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_TabS1_The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse

Author Weingartner, Michael; Stücheli, Simon; Kratschmar, Denise V; Birk, Julia; Klusonova, Petra; Chapman, Karen E; Lavery, Gareth G; Odermatt, Alex
Publication date 30.08.2021
Persistent Identifier (PID) 10.5281/zenodo.4536960
Repository Zenodo
Abstract
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

Data_Figure1_Development and Validation of a Highly Sensitive LC-MS/MS Method for the Analysis of Bile Acids in Serum, Plasma, and Liver Tissue Samples

Author Gómez, Cristina; Stücheli, Simon; Kratschmar, Denise V; Bouitbir, Jamal; Odermatt, Alex
Publication date 09.07.2020
Persistent Identifier (PID) 10.5281/zenodo.4528949
Repository Zenodo
Abstract
Bile acids control lipid homeostasis by regulating uptake from food and excretion. Additionally, bile acids are bioactive molecules acting through receptors and modulating various physiological processes. Impaired bile acid homeostasis is associated with several diseases and drug-induced liver injury. Individual bile acids may serve as disease and drug toxicity biomarkers, with a great demand for improved bile acid quantification methods. We developed, optimized, and validated an LC-MS/MS method for quantification of 36 bile acids in serum, plasma, and liver tissue samples. The simultaneous quantification of important free and taurine- and glycine-conjugated bile acids of human and rodent species has been achieved using a simple workflow. The method was applied to a mouse model of statin-induced myotoxicity to assess a possible role of bile acids. Treatment of mice for three weeks with 5, 10, and 25 mg/kg/d simvastatin, causing adverse skeletal muscle effects, did not alter plasma and liver tissue bile acid profiles, indicating that bile acids are not involved in statin-induced myotoxicity. In conclusion, the established LC-MS/MS method enables uncomplicated sample preparation and quantification of key bile acids in serum, plasma, and liver tissue of human and rodent species to facilitate future studies of disease mechanisms and drug-induced liver injury.

Data_Figure2_Development and Validation of a Highly Sensitive LC-MS/MS Method for the Analysis of Bile Acids in Serum, Plasma, and Liver Tissue Samples

Author Gómez, Cristina; Stücheli, Simon; Kratschmar, Denise V; Bouitbir, Jamal; Odermatt, Alex
Publication date 09.07.2020
Persistent Identifier (PID) 10.5281/zenodo.4528982
Repository Zenodo
Abstract
Bile acids control lipid homeostasis by regulating uptake from food and excretion. Additionally, bile acids are bioactive molecules acting through receptors and modulating various physiological processes. Impaired bile acid homeostasis is associated with several diseases and drug-induced liver injury. Individual bile acids may serve as disease and drug toxicity biomarkers, with a great demand for improved bile acid quantification methods. We developed, optimized, and validated an LC-MS/MS method for quantification of 36 bile acids in serum, plasma, and liver tissue samples. The simultaneous quantification of important free and taurine- and glycine-conjugated bile acids of human and rodent species has been achieved using a simple workflow. The method was applied to a mouse model of statin-induced myotoxicity to assess a possible role of bile acids. Treatment of mice for three weeks with 5, 10, and 25 mg/kg/d simvastatin, causing adverse skeletal muscle effects, did not alter plasma and liver tissue bile acid profiles, indicating that bile acids are not involved in statin-induced myotoxicity. In conclusion, the established LC-MS/MS method enables uncomplicated sample preparation and quantification of key bile acids in serum, plasma, and liver tissue of human and rodent species to facilitate future studies of disease mechanisms and drug-induced liver injury.

Data_Figure3_Development and Validation of a Highly Sensitive LC-MS/MS Method for the Analysis of Bile Acids in Serum, Plasma, and Liver Tissue Samples

Author Gómez, Cristina; Stücheli, Simon; Kratschmar, Denise V; Bouitbir, Jamal; Odermatt, Alex
Publication date 09.07.2020
Persistent Identifier (PID) 10.5281/zenodo.4529014
Repository Zenodo
Abstract
Bile acids control lipid homeostasis by regulating uptake from food and excretion. Additionally, bile acids are bioactive molecules acting through receptors and modulating various physiological processes. Impaired bile acid homeostasis is associated with several diseases and drug-induced liver injury. Individual bile acids may serve as disease and drug toxicity biomarkers, with a great demand for improved bile acid quantification methods. We developed, optimized, and validated an LC-MS/MS method for quantification of 36 bile acids in serum, plasma, and liver tissue samples. The simultaneous quantification of important free and taurine- and glycine-conjugated bile acids of human and rodent species has been achieved using a simple workflow. The method was applied to a mouse model of statin-induced myotoxicity to assess a possible role of bile acids. Treatment of mice for three weeks with 5, 10, and 25 mg/kg/d simvastatin, causing adverse skeletal muscle effects, did not alter plasma and liver tissue bile acid profiles, indicating that bile acids are not involved in statin-induced myotoxicity. In conclusion, the established LC-MS/MS method enables uncomplicated sample preparation and quantification of key bile acids in serum, plasma, and liver tissue of human and rodent species to facilitate future studies of disease mechanisms and drug-induced liver injury.

Data_Tab1_Development and Validation of a Highly Sensitive LC-MS/MS Method for the Analysis of Bile Acids in Serum, Plasma, and Liver Tissue Samples

Author Gómez, Cristina; Stücheli, Simon; Kratschmar, Denise V; Bouitbir, Jamal; Odermatt, Alex
Publication date 09.07.2020
Persistent Identifier (PID) 10.5281/zenodo.4529044
Repository Zenodo
Abstract
Bile acids control lipid homeostasis by regulating uptake from food and excretion. Additionally, bile acids are bioactive molecules acting through receptors and modulating various physiological processes. Impaired bile acid homeostasis is associated with several diseases and drug-induced liver injury. Individual bile acids may serve as disease and drug toxicity biomarkers, with a great demand for improved bile acid quantification methods. We developed, optimized, and validated an LC-MS/MS method for quantification of 36 bile acids in serum, plasma, and liver tissue samples. The simultaneous quantification of important free and taurine- and glycine-conjugated bile acids of human and rodent species has been achieved using a simple workflow. The method was applied to a mouse model of statin-induced myotoxicity to assess a possible role of bile acids. Treatment of mice for three weeks with 5, 10, and 25 mg/kg/d simvastatin, causing adverse skeletal muscle effects, did not alter plasma and liver tissue bile acid profiles, indicating that bile acids are not involved in statin-induced myotoxicity. In conclusion, the established LC-MS/MS method enables uncomplicated sample preparation and quantification of key bile acids in serum, plasma, and liver tissue of human and rodent species to facilitate future studies of disease mechanisms and drug-induced liver injury.

Data_Tab2_Development and Validation of a Highly Sensitive LC-MS/MS Method for the Analysis of Bile Acids in Serum, Plasma, and Liver Tissue Samples

Author Gómez, Cristina; Stücheli, Simon; Kratschmar, Denise V; Bouitbir, Jamal; Odermatt, Alex
Publication date 09.07.2020
Persistent Identifier (PID) 10.5281/zenodo.4529161
Repository Zenodo
Abstract
Bile acids control lipid homeostasis by regulating uptake from food and excretion. Additionally, bile acids are bioactive molecules acting through receptors and modulating various physiological processes. Impaired bile acid homeostasis is associated with several diseases and drug-induced liver injury. Individual bile acids may serve as disease and drug toxicity biomarkers, with a great demand for improved bile acid quantification methods. We developed, optimized, and validated an LC-MS/MS method for quantification of 36 bile acids in serum, plasma, and liver tissue samples. The simultaneous quantification of important free and taurine- and glycine-conjugated bile acids of human and rodent species has been achieved using a simple workflow. The method was applied to a mouse model of statin-induced myotoxicity to assess a possible role of bile acids. Treatment of mice for three weeks with 5, 10, and 25 mg/kg/d simvastatin, causing adverse skeletal muscle effects, did not alter plasma and liver tissue bile acid profiles, indicating that bile acids are not involved in statin-induced myotoxicity. In conclusion, the established LC-MS/MS method enables uncomplicated sample preparation and quantification of key bile acids in serum, plasma, and liver tissue of human and rodent species to facilitate future studies of disease mechanisms and drug-induced liver injury.

Data_Supplemental_Figure1_Development and Validation of a Highly Sensitive LC-MS/MS Method for the Analysis of Bile Acids in Serum, Plasma, and Liver Tissue Samples

Author Gómez, Cristina; Stücheli, Simon; Kratschmar, Denise V; Bouitbir, Jamal; Odermatt, Alex
Publication date 09.07.2020
Persistent Identifier (PID) 10.5281/zenodo.4529169
Repository Zenodo
Abstract
Bile acids control lipid homeostasis by regulating uptake from food and excretion. Additionally, bile acids are bioactive molecules acting through receptors and modulating various physiological processes. Impaired bile acid homeostasis is associated with several diseases and drug-induced liver injury. Individual bile acids may serve as disease and drug toxicity biomarkers, with a great demand for improved bile acid quantification methods. We developed, optimized, and validated an LC-MS/MS method for quantification of 36 bile acids in serum, plasma, and liver tissue samples. The simultaneous quantification of important free and taurine- and glycine-conjugated bile acids of human and rodent species has been achieved using a simple workflow. The method was applied to a mouse model of statin-induced myotoxicity to assess a possible role of bile acids. Treatment of mice for three weeks with 5, 10, and 25 mg/kg/d simvastatin, causing adverse skeletal muscle effects, did not alter plasma and liver tissue bile acid profiles, indicating that bile acids are not involved in statin-induced myotoxicity. In conclusion, the established LC-MS/MS method enables uncomplicated sample preparation and quantification of key bile acids in serum, plasma, and liver tissue of human and rodent species to facilitate future studies of disease mechanisms and drug-induced liver injury.

Data_Supplemental_Tab1_Development and Validation of a Highly Sensitive LC-MS/MS Method for the Analysis of Bile Acids in Serum, Plasma, and Liver Tissue Samples

Author Gómez, Cristina; Stücheli, Simon; Kratschmar, Denise V; Bouitbir, Jamal; Odermatt, Alex
Publication date 09.07.2020
Persistent Identifier (PID) 10.5281/zenodo.4529182
Repository Zenodo
Abstract
Bile acids control lipid homeostasis by regulating uptake from food and excretion. Additionally, bile acids are bioactive molecules acting through receptors and modulating various physiological processes. Impaired bile acid homeostasis is associated with several diseases and drug-induced liver injury. Individual bile acids may serve as disease and drug toxicity biomarkers, with a great demand for improved bile acid quantification methods. We developed, optimized, and validated an LC-MS/MS method for quantification of 36 bile acids in serum, plasma, and liver tissue samples. The simultaneous quantification of important free and taurine- and glycine-conjugated bile acids of human and rodent species has been achieved using a simple workflow. The method was applied to a mouse model of statin-induced myotoxicity to assess a possible role of bile acids. Treatment of mice for three weeks with 5, 10, and 25 mg/kg/d simvastatin, causing adverse skeletal muscle effects, did not alter plasma and liver tissue bile acid profiles, indicating that bile acids are not involved in statin-induced myotoxicity. In conclusion, the established LC-MS/MS method enables uncomplicated sample preparation and quantification of key bile acids in serum, plasma, and liver tissue of human and rodent species to facilitate future studies of disease mechanisms and drug-induced liver injury.

Data_Supplemental_Tab2_Development and Validation of a Highly Sensitive LC-MS/MS Method for the Analysis of Bile Acids in Serum, Plasma, and Liver Tissue Samples

Author Gómez, Cristina; Stücheli, Simon; Kratschmar, Denise V; Bouitbir, Jamal; Odermatt, Alex
Publication date 09.07.2020
Persistent Identifier (PID) 10.5281/zenodo.4529188
Repository Zenodo
Abstract
Bile acids control lipid homeostasis by regulating uptake from food and excretion. Additionally, bile acids are bioactive molecules acting through receptors and modulating various physiological processes. Impaired bile acid homeostasis is associated with several diseases and drug-induced liver injury. Individual bile acids may serve as disease and drug toxicity biomarkers, with a great demand for improved bile acid quantification methods. We developed, optimized, and validated an LC-MS/MS method for quantification of 36 bile acids in serum, plasma, and liver tissue samples. The simultaneous quantification of important free and taurine- and glycine-conjugated bile acids of human and rodent species has been achieved using a simple workflow. The method was applied to a mouse model of statin-induced myotoxicity to assess a possible role of bile acids. Treatment of mice for three weeks with 5, 10, and 25 mg/kg/d simvastatin, causing adverse skeletal muscle effects, did not alter plasma and liver tissue bile acid profiles, indicating that bile acids are not involved in statin-induced myotoxicity. In conclusion, the established LC-MS/MS method enables uncomplicated sample preparation and quantification of key bile acids in serum, plasma, and liver tissue of human and rodent species to facilitate future studies of disease mechanisms and drug-induced liver injury.

Data_Fig5_Inhibition of IL-1beta improves Glycaemia in a Mouse Model for Gestational Diabetes

Author Schulze, Friederike; Wehner, Josua; Kratschmar, Denise V; Makshana, Valmir; Meier, Daniel T; Häuselmann, Stéphanie P; Dalmas, Elise; Thienel, Constanze; Dror, Erez; Wiedemann, Sophia J; Traub, Shuyang; Nordmann, Thierry M; Rachid, Leila; De Baat, Axel; Rohm, Theresa V; Zhao, Cheng; Odermatt, Alex; Böni-Schnetzler, Marianne; Donath, Marc Y
Publication date 20.03.2020
Persistent Identifier (PID) 10.5281/zenodo.5509903
Repository Zenodo
Abstract
Gestational diabetes mellitus (GDM) is one of the most common diseases associated with pregnancy, however, the underlying mechanisms remain unclear. Based on the well documented role of inflammation in type 2 diabetes, the aim was to investigate the role of inflammation in GDM. We established a mouse model for GDM on the basis of its two major risk factors, obesity and aging. In these GDM mice, we observed increased Interleukin-1β (IL-1β) expression in the uterus and the placenta along with elevated circulating IL-1β concentrations compared to normoglycemic pregnant mice. Treatment with an anti-IL-1β antibody improved glucose-tolerance of GDM mice without apparent deleterious effects for the fetus. Finally, IL-1β antagonism showed a tendency for reduced plasma corticosterone concentrations, possibly explaining the metabolic improvement. We conclude that IL-1β is a causal driver of impaired glucose tolerance in GDM.

Data_Fig4_Loss of Claudin-3 Impairs Hepatic Metabolism, Biliary Barrier Function, and Cell Proliferation in the Murine Liver

Author Baier, Felix Alexander; Sánchez-Taltavull, Daniel; Yarahmadov, Tural; Castellà, Cristina Gómez; Jebbawi, Fadi; Keogh, Adrian; Tombolini, Riccardo; Odriozola, Adolfo; Dias, Mariana Castro; Deutsch, Urban; Furuse, Mikio; Engelhardt, Britta; Zuber, Benoît; Odermatt, Alex; Candinas, Daniel; Stroka, Deborah
Publication date 01.01.2021
Persistent Identifier (PID) 10.1016/j.jcmgh.2021.04.003
Repository zenodo


Data_Tab1_Deletion of the transcription factor Prox-1 specifically in the renal distal convoluted tubule causes hypomagnesemia via reduced expression of TRPM6 and NCC

Author Schnoz, Christina; Moser, Sandra; Kratschmar, Denise V; Odermatt, Alex; Loffing-Cueni, Dominique; Loffing, Johannes
Publication date 02.03.2021
Persistent Identifier (PID) 10.5281/zenodo.5516939
Repository Zenodo
Abstract
homeostasis in the adult kidney.

Collaboration

Group / person Country
Types of collaboration
Marc Donath/University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Reto Portmann/Agroscope Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Deborah Stroka/University Hospital Berne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Ruth Morgan/University of Edinburgh Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Anton Jetten/NIEHS Research Triangle Park United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Gareth Lavery/Nothingham Trent University Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Salvatore Piscuoglio/Pathology Institute Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Sloan Devlin/Harvard University Boston United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Eric Sheu/Harvard University Boston United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual Meeting 2021 of the Swiss Society of Toxicology Poster Activation of retinoic acid-related orphan receptor γt by parabens and UV-filters 18.11.2021 Basel, Switzerland Odermatt Alexander;
Annual meeting 2021 of the Swiss Society of Toxicology Poster Biological evaluation of steroid 11β-hydroxylase inhibitors identified by virtual screening 18.11.2021 Basel, Switzerland Odermatt Alexander;
Toyoma-Basel Research Meeting - online Poster Species specific differences in the inhibition of 11ß-hydroxysteroid dehydrogenase 2 by itraconazole 15.09.2021 Basel, Toyoma, Switzerland Zogg Michael; Odermatt Alexander;
Toyama-Basel Research Meeting - online Poster Profiling of azole fungicides for interferences with steroidogenesis 15.09.2021 Basel, Toyama, Switzerland Odermatt Alexander;
DGPT course "Xenobiotic metabolism/toxicokinetics" Talk given at a conference Dehydrogenases 31.08.2021 online, Switzerland Odermatt Alexander;
Swiss Society of Pharmacology and Toxicology / GENE AND CELL THERAPY Talk given at a conference Species-specific differences in the inhibition of 11ß-hydroxysteroid dehydrogenase 2 by intraconazole 15.04.2021 online, Switzerland Zogg Michael; Odermatt Alexander;
Swiss Society of Pharmacology and Toxicology / GENE AND CELL THERAPY Talk given at a conference Effects of clinically used azole fungicides on adrenal steroid profiles 15.04.2021 online, Switzerland Odermatt Alexander;
Annual Meeting 2020 of the Swiss Society of Toxicology Poster Species-specific differences in the inhibition of 11ß-hydroxysteroid dehydrogenase 2 by intraconazole 29.01.2021 online, Switzerland Odermatt Alexander; Zogg Michael;
SST Annual Meeting 2019 Talk given at a conference Azole fungicide-induced hypertension and hypokalemia 28.11.2019 Basel, Switzerland Odermatt Alexander;
Swiss Steroid Symposium 2019 Talk given at a conference 11β-hydroxysteroid dehydrogenases: novel roles in oxysterol metabolism 21.11.2019 Bern, Switzerland Odermatt Alexander;
Research Seminars at Paracelsus Medical University Individual talk “Drug-induced hypertension and hypokalemia due to mineralocorticoid excess” 05.11.2019 Salzburg, Austria Odermatt Alexander;
1. Studierendenkonferenz der angewandten instrumentellen Analytik, Paracelsus Medizinische Privatuniversität Talk given at a conference "Quantifizierung von Steroiden: Vergleich von Massenspektrometrie und konventionellen Methoden" 05.11.2019 Salzburg, Austria Odermatt Alexander;
NIBR Weekly Seminar Series Individual talk Exploring the substrate specificities of short-chain dehydrogenase/ reductase enzymes: opening novel opportunities? Exemplified on 11beta-hydroxysteroid dehydrogenases 22.10.2019 Basel, Switzerland Odermatt Alexander;
ENOR - Symposium 2019 Talk given at a conference The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse 19.09.2019 Edinburgh, Great Britain and Northern Ireland Odermatt Alexander;
ENOR - Symposium 2019 Poster 11β-Hydroxysteroid Dehydrogenases control 7β,27-dihydroxycholesterol access to retinoic acid-related orphan receptor gamma 19.09.2019 Edinburgh, Great Britain and Northern Ireland Odermatt Alexander; Beck Katharina;
Einweihung 4. Reinigungsstufe auf der ARA Altenrhein Individual talk «Steroidhormone als Therapeutika und unerwünschte Effekte» 05.09.2019 Altenrhein, Switzerland Odermatt Alexander;
DGPT course "Xenobiotic metabolism/toxicokinetics" Talk given at a conference Dehydrogenases 27.08.2019 Zürich, Switzerland Odermatt Alexander;
CAS du CRCT - research seminar - University of Toulouse Individual talk Role of 11β-hydroxysteroid dehydrogenase enzymes in oxysterol and bile acid metabolism 15.02.2019 Toulouse, France Odermatt Alexander;
Annual Research Meeting of Swiss Society of Toxicology Poster Profiling of anabolic androgenic steroids and selective androgen receptor modulators for interference with adrenocortical steroidogenesis 30.11.2018 Basel, Switzerland Odermatt Alexander; Beck Katharina;
DGPT "Xenobiotic metabolism/toxicokinetics" Talk given at a conference Dehydrogenases 28.08.2018 Zürich, Switzerland Odermatt Alexander;
CSR 2018 - 4th Congress on Steroid Research Poster Identification of epoxiconazole as CYP11B1/2 inhibitor by virtual screening and biological assessment in adrenal H295R cells 10.07.2018 Seoul, Korean Republic (South Korea) Odermatt Alexander;
Paracelsus Science Get Together Poster The anti-fungal epoxiconazole inhibits human CYP11B1 and CYP11B2: Virtual screening as a tool to find potential endocrine disruptors 29.06.2018 Salzburg, Austria Odermatt Alexander;


Self-organised

Title Date Place
Annual Meeting 2020 of the Swiss Society of Toxicology 28.01.2021 Basel (online), Switzerland
CSR 2018 - 4th Congress on Steroid Research 08.07.2018 Seoul, Korean Republic (South Korea)

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Bagatellerkrankungen im Enzug- Ursachen und Behandlung Talk 21.06.2018 Kriens, Switzerland Weingartner Michael;
Bagatellerkrankungen im Enzug- Ursachen und Behandlung Talk 24.05.2018 Kriens (LU), Switzerland Weingartner Michael;


Awards

Title Year
Irma Tschudi-Steiner Preis für die beste Dissertation einer Nachwuchspharmazeutin an der Uni Basel "Small molecule-protein interactions exemplified on short-chain dehydrogenases/reductases" 2019

Associated projects

Number Title Start Funding scheme
159454 Impact of the NADPH pool in the endoplasmic reticulum on metabolic and hormonal regulation 01.05.2015 Project funding (Div. I-III)
159454 Impact of the NADPH pool in the endoplasmic reticulum on metabolic and hormonal regulation 01.05.2015 Project funding (Div. I-III)

Abstract

An impaired redox control in the endoplasmic reticulum (ER) with unfolded-protein response (UPR) and ER-stress has been associated with major diseases such as cancer, cardio-metabolic disorders, and chronic inflammatory diseases. Thus, it is crucial to elucidate the mechanisms underlying ER-redox control and identify involved modulators and biological reactions. The NAD(P)H/NAD(P)+ redox couple is essential for many biological functions and, in contrast to the cytoplasm, its regulation in the ER and the relevance of luminal NADPH for physiological functions such as intracellular calcium signaling, UPR control, and the metabolism of glucose, fatty acids, oxysterols, and glucocorticoids is insufficiently understood. The discovery of hexose-6-phosphate dehydrogenase (H6PDH) revealed a mechanism for luminal NADPH generation and provided a link between energy status and glucocorticoid signaling. To date, 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) is still the only well characterized NADPH-dependent luminal enzyme. Besides its well-known role in glucocorticoid activation and involvement in metabolic and inflammatory diseases, increasing evidence revealed a role of 11ß-HSD1 in oxysterol and bile acid metabolism, warranting further studies. Moreover, there must be other NADPH-dependent enzymes because 11ß-HSD1 cannot account for the myopathy and increased susceptibility of hepatocytes toward toxicants observed in situations of H6PDH-deficiency.Based on previous results, we hypothesize that 1) the ratios of certain bile acids serve as potential prognostic markers for decreased 11ß-HSD1 activity in rodents and human, 2) 11ß-HSD1 is involved in the formation of dihydroxylated oxysterols that modulate the activities of nuclear receptors (ROR, ERß, LXRß) and the G-coupled receptor EBI2, 3) H6PDH delivers NADPH for fatty acid elongation in the ER, which is needed for rapid cell proliferation, 4) loss of H6PDH affects UPR and renders cells susceptible to substances causing ER-stress, and 5) other enzymes generating and utilizing NADPH in the ER exist and need to be identified and characterized.To study the consequences of ER NADPH depletion on hormonal and metabolic functions, and to identify and characterize novel modulators of luminal NADPH, we propose to:•evaluate whether ratios of certain 7oxo to 7ß-hydroxy bile acids in plasma/serum can serve as markers for reduced 11ß-HSD1 activity in human,•further explore the role of 11ß-HSD1 in oxysterol and bile acid metabolism and the modulation of cognate receptors,•study other enzymes generating or utilizing NADPH in the ER,•study the impact of H6PDH on fatty acid synthesis/metabolism,•investigate the impact of H6PDH on breast cancer cell properties,•study the susceptibility of H6PDH-deficient primary liver and kidney cells to ER-stress, and•explore the use of IP-MS and BioID to investigate protein-protein interactions in the ER.Steroids and other lipophilic compounds in different matrices will be quantified using LC-MS/MS. The role of luminal NADPH and consequences of its depletion on metabolic and hormonal responses will be studied using enzyme preparations, cell-based models upon modulating the corresponding enzyme(s) by overexpression, downregulation by siRNA or pharmacological inhibition. Further, studies in transgenic mice and mice treated with inhibitors and in primary cells will be performed. Also, protein interaction methods will be employed, attempting to identify novel players in ER NADPH regulation. The proposed research should significantly enhance our current knowledge on the role of NADPH in the ER. The expected findings are relevant to understand the coupling between cellular energy state, hormonal regulation, ER redox regulation, and oxidative stress-induced damage. Disturbed functions of the enzymes studied are associated with impaired inflammatory responses, cardio-metabolic disorders and cancer, and the results of the proposed project should support the future development of therapeutic interventions.
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