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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 159454
Funding scheme Project funding
Research institution Universität Basel
Institution of higher education University of Basel - BS
Main discipline Biochemistry
Start/End 01.05.2015 - 30.04.2018
Approved amount 582'205.00
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All Disciplines (2)

Discipline
Biochemistry
Endocrinology

Keywords (10)

11beta-hydroxysteroid dehydrogenase; glucose-6-phosphate; redox; oxysterol; macrophage; endoplasmic reticulum; glucocorticoid; bile acid; hexose-6-phosphate dehydrogenase; NADPH

Lay Summary (German)

Lead
Regulation von Reduktionsreaktionen im Endoplasmatischen Retikulum und deren Einfluss auf Metabolismus und Hormonwirkungen
Lay summary

Eine gestörte Kontrolle der Reduktionsreaktionen im endoplasmatischen Retikulum (ER) kann zu Problemen in der Proteinfaltung führen, was ER-Stress verursachen und zur Entstehung von verschiedenen Krankheiten wie Diabetes, Arteriosklerose und Krebs beitragen kann. Die Aufklärung der Mechanismen, die verantwortlich sind für die Kontrolle von Reduktionsäquivalenten im ER, sowie die Identifizierung der darin involvierten Proteinen soll zum Verständnis grundlegender Prozesse im Energiehaushalt einer Zelle und deren Adaptation an veränderte Bedingungen beitragen.

Im vorliegenden Projekt wird die Rolle des Reduktionsäquivalents NADPH im ER in verschiedenen Zelltypen untersucht. Der Einfluss einer veränderten ER luminalen NADPH Konzentration auf die Polarisierung und Funktion von Makrophagen und dendritischen Zellen soll entschlüsselt werden. Dabei werden Glucocorticoid abhängige und unabhängige Prozesse angeschaut. Im Weiteren soll der Einfluss von NADPH im ER auf den Metabolismus von Oxysterolen und Gallensäuren studiert werden. Experimente werden dabei in Zellen sowie in Mäusen durchgeführt, um die physiologische Relevanz der Ergebnisse aus Zellversuchen zu unterstützen. Neben Makrophagen soll der Einfluss von ER luminalem NADPH auch in Leberzellen auf den Oxysterol- und Gallensäurenstoffwechsel untersucht werden. Da bisher erst ein Enzym, das ER luminales NADPH benötigt, ausführlich untersucht wurde, ist ein weiteres Ziel des vorliegenden Projekts die Entdeckung weiterer Enzyme im ER, die durch NADPH in ihrer Aktivität stimuliert werden. Hinweise auf zwei Enzyme mit einer Rolle im Lipidstoffwechsel ergaben sich aus den Resultaten des vorangehenden Projekts.

Die zu erwartenden Ergebnisse der geplanten Experimente sollen zu einem verbesserten Verständnis der hormonellen Regulation des Energiestoffwechsels und des Einflusses von NADPH im ER auf hormonelle und metabolische Funktionen beitragen, mit Relevanz hinsichtlich Entzündungskrankheiten und kardiometabolische Erkrankungen.    

Direct link to Lay Summary Last update: 24.04.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
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.
Currently available murine Leydig cell lines can be applied to study early steps of steroidogenesis but not testosterone synthesis.
Engeli R. T. Fürstenberger C. Kratschmar D. V. and Odermatt A. (2018), Currently available murine Leydig cell lines can be applied to study early steps of steroidogenesis but not testosterone synthesis., in Heliyon, 4, e00527.
Hexose-6-phosphate dehydrogenase controls cancer cell proliferation and migration through pleiotropic effects on the unfolded protein response, calcium homeostasis and redox balance.
Tsachaki M. Mladenovic N. Stambergova H. Birk J. and Odermatt A. (2018), Hexose-6-phosphate dehydrogenase controls cancer cell proliferation and migration through pleiotropic effects on the unfolded protein response, calcium homeostasis and redox balance., in FASEB J, 32, 2690-2705.
Biochemical Analysis of Four Missense Mutations in the HSD17B3 Gene Associated With 46,XY Disorders of Sex Development in Egyptian Patients
Engeli Roger T., Tsachaki Maria, Hassan Heba A., Sager Christoph P., Essawi Mona L., Gad Yehia Z., Kamel Alaa K., Mazen Inas, Odermatt Alex (2017), Biochemical Analysis of Four Missense Mutations in the HSD17B3 Gene Associated With 46,XY Disorders of Sex Development in Egyptian Patients, in Journal of Sexual Medicine, 14(9), 1165-1174.
DHRS7 (SDR34C1) – A new player in the regulation of androgen receptor function by inactivation of 5α-dihydrotestosterone?
Araya Selene, Kratschmar Denise V., Tsachaki Maria, Stücheli Simon, Beck Katharina R., Odermatt Alex (2017), DHRS7 (SDR34C1) – A new player in the regulation of androgen receptor function by inactivation of 5α-dihydrotestosterone?, in Journal of Steroid Biochemistry and Molecular Biology, 171, 288-295.
Virtual screening applications in short-chain dehydrogenase/reductase research
Beck Katharina R., Kaserer Teresa, Schuster Daniela, Odermatt Alex (2017), Virtual screening applications in short-chain dehydrogenase/reductase research, in Journal of Steroid Biochemistry and Molecular Biology, 171, 157-177.
Fructose, glucocorticoids and adipose tissue: Implications for the metabolic syndrome
Legeza Balázs, Marcolongo Paola, Gamberucci Alessandra, Varga Viola, Bánhegyi Gábor, Benedetti Angiolo, Odermatt Alex (2017), Fructose, glucocorticoids and adipose tissue: Implications for the metabolic syndrome, in Nutrients, 9(5), 426.
Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2
Vuorinen Anna, Engeli Roger T., Leugger Susanne, Bachmann Fabio, Akram Muhammad, Atanasov Atanas G., Waltenberger Birgit, Temml Veronika, Stuppner Hermann, Krenn Liselotte, Ateba Sylvin B., Njamen Dieudonné, Davis Rohan A., Odermatt Alex, Schuster Daniela (2017), Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2, in Journal of Natural Products, 80(4), 965-974.
Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole
Beck Katharina R., Bächler Murielle, Vuorinen Anna, Wagner Sandra, Akram Muhammad, Griesser Ulrich, Temml Veronika, Klusonova Petra, Yamaguchi Hideaki, Schuster Daniela, Odermatt Alex (2017), Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole, in Biochemical Pharmacology, 130, 93-103.
Absence of 11-keto reduction of cortisone and 11-ketotestosterone in the model organism zebrafish
Tsachaki Maria, Meyer Arne, Weger Benjamin, Tokarz Janina, Adamski Jerzy, Belting Heinz-Georg, Affolter Markus, Dickmeis Thomas, Odermatt Alex (2017), Absence of 11-keto reduction of cortisone and 11-ketotestosterone in the model organism zebrafish, in Journal of Endocrinology, 232, 323-335.
Carbonyl reductase 1 catalyzes 20beta-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity
Morgan R A, Beck K R, Nixon M, Homer N Z M, Crawford A A, Melchers D, Houtman R, Meijer O C, Stomby A, Anderson A J, Upreti R H, Olsson T, Michoel T, Cohain A, Ruusalepp A, Schadt E E, Björkegren J L M, Andrew R, Kenyon C J, Hadoke P W F, Odermatt A, Keen J A, Walker B R (2017), Carbonyl reductase 1 catalyzes 20beta-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity, in Scientific Reports, 7, 10633.
Novel 11β-hydroxysteroid dehydrogenase 1 inhibitors reduce cortisol levels in keratinocytes and improve dermal collagen content in human ex vivo skin after exposure to cortisone and UV
Boudon S M, Vuorinen A, Geotti-Bianchini P, Wandeler E, Kratschmar D V, Heidl M, Campiche R, Jackson E, Odermatt A (2017), Novel 11β-hydroxysteroid dehydrogenase 1 inhibitors reduce cortisol levels in keratinocytes and improve dermal collagen content in human ex vivo skin after exposure to cortisone and UV, in Plos One, 12, e0171079.
Phenylbenzenesulfonates and -sulfonamides as 17β-hydroxysteroid dehydrogenase type 2 inhibitors: Synthesis and SAR-analysis
Vuorinen Anna, Engeli Roger T., Leugger Susanne, Kreutz Christoph R., Schuster Daniela, Odermatt Alex, Matuszczak Barbara (2016), Phenylbenzenesulfonates and -sulfonamides as 17β-hydroxysteroid dehydrogenase type 2 inhibitors: Synthesis and SAR-analysis, in Bioorganic and Medicinal Chemistry Letters, 27(13), 2982-2985.
Biochemical analyses and molecular modeling explain the functional loss of 17β-hydroxysteroid dehydrogenase 3 mutant G133R in three Tunisian patients with 46, XY disorders of sex development
Engeli RT Ben Rhouma B Sager CP Tsachaki M Birk J Fakhfakh F Keskes L Belguith N Odermatt A (2016), Biochemical analyses and molecular modeling explain the functional loss of 17β-hydroxysteroid dehydrogenase 3 mutant G133R in three Tunisian patients with 46, XY disorders of sex development, in J. Steroid Biochem. Mol. Biol., 155, 147-154.
Disruption of steroidogenesis: cell models for mechanistic investigations and as screening tools
Odermatt A. Strajhar P. Engeli R. T (2016), Disruption of steroidogenesis: cell models for mechanistic investigations and as screening tools, in J Steroid Biochem Mol Biol, 158, 9-21.
Role of Pro-637 and Gln-642 in human glucocorticoid receptors and Ser-843 and Leu-848 in mineralocorticoid receptors in their differential responses to cortisol and aldosterone.
Mani Orlando, Nashev Lyubomir, Livelo Chris, Baker Michael E, Odermatt Alex (2016), Role of Pro-637 and Gln-642 in human glucocorticoid receptors and Ser-843 and Leu-848 in mineralocorticoid receptors in their differential responses to cortisol and aldosterone., in J Steroid Biochem Mol Biol, 159, 31-40.
A role for the dehydrogenase DHRS7 (SDR34C1) in prostate cancer
Seibert J. K. Quagliata L. Quintavalle C. Hammond T. G. Terracciano L. Odermatt A (2015), A role for the dehydrogenase DHRS7 (SDR34C1) in prostate cancer, in Cancer Medicine, 4, 1717-1729.

Collaboration

Group / person Country
Types of collaboration
Brian Walker/University of Edinburgh Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Daniela Schuster/University of Innsbruck Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Klaus Seuwen Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Industry/business/other use-inspired collaboration
Gareth Lavery Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Stephan Krähenbühl/Universität Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Michael Baker/UCSD United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Michael Witting/Helmholtz Zentrum München Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Jeremy Tomlinson/Oxford University Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Luigi Terracciano/Universität Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Henriette Meyer zu Schwabedissen/Universität Basel Switzerland (Europe)
- Research Infrastructure
Jörg Huwyler/Universität Basel Switzerland (Europe)
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
100th Endocrine Society Annual Meeting ENDO 2018 Talk given at a conference Modulators of 11β-HSD2 Function: Impact on Corticosteroid Receptors 20.03.2018 Chicago, United States of America Odermatt Alexander;
100th Endocrine Society Annual Meeting ENDO2018 Poster Role of Hexose-6-phosphate dehydrogenase in cancer cell proliferation and migration 19.03.2018 Chicago, United States of America Odermatt Alexander;
Annual Meeting Swiss Society of Toxicology 2017 Poster Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole 30.11.2017 Basel, Switzerland Beck Katharina; Klusonova Petra; Odermatt Alexander;
Annual Meeting Swiss Society of Toxicology 2017 Poster Characterization of murine Leydig Cells as Potential Screening Tool for Disruption of Androgen Synthesis by Xenobiotics 30.11.2017 Basel, Switzerland Odermatt Alexander;
DGPT training course "xenobiotic metabolism/toxicokinetics" Talk given at a conference Dehydrogenases 30.08.2017 Zürich, Switzerland Odermatt Alexander;
18th European Congress of Endocrinology Poster Identification of chemicals disrupting adrenal steroid production by steroid profiling in H295R cells 20.05.2017 Lisbon, Portugal Odermatt Alexander;
18th European Congress of Endocrinology Poster Strategy towards the identification of novel substrates of short-chain dehydrogenases/reductases as exemplified on 11β-HSD1 20.05.2017 Lisbon, Portugal Beck Katharina; Odermatt Alexander;
18th European Congress of Endocrinology Poster Characterization of Murine Leydig Cell Lines as Tools to Study Androgen Synthesis Disruption by Xenobiotics 20.05.2017 Lisbon, Portugal Odermatt Alexander;
Annual Meeting British Society of Toxicology 2017 Poster Association of the Short-Chain Dehydrogenase/Reductase Enzyme DHRS7 (SDR34C1) with the Pathogenesis of Prostate Cancer – Could Inhibition of This Enzyme by Xenobiotics Represent a Risk for Non-Genotoxic Carcinogenicity? 03.04.2017 Liverpool, Great Britain and Northern Ireland Araya Selene; Beck Katharina; Odermatt Alexander;
Eurotox 2016 Congress Poster Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole 04.09.2016 Seville, Spain Odermatt Alexander; Klusonova Petra; Beck Katharina;
DGPT training course "xenobiotic metabolism/toxicokinetics" Talk given at a conference Dehydrogenases 30.08.2016 Zürich, Switzerland Odermatt Alexander;
36th Colloquium on Toxicology, Swiss Society of Toxicology Talk given at a conference In vitro analysis of endocrine active chemicals: Know your system! 16.08.2016 Basel, Switzerland Odermatt Alexander;
Pharma and Food, Lecture Series Individual talk Selectivity of oxidoreductase inhibitors: what we can learn from natural products 12.05.2016 Vienna, Austria Odermatt Alexander;
Swiss Society of Pharmacology and Toxicology, Spring Meeting 2016 Poster Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole 21.04.2016 Bern, Switzerland Klusonova Petra; Beck Katharina; Odermatt Alexander;
Swiss Society of Pharmacology and Toxicology, Spring Meeting 2016 Poster Intracellular localization and search for a function of the potential tumor suppressor enzyme DHRS7 (SDR34C1) 21.04.2016 Bern, Switzerland Araya Selene; Odermatt Alexander;
Swiss Society of Pharmacology and Toxicology, Spring Meeting 2016 Poster Natural products as a rich source for potential anti‐osteoporotic lead agents inhibiting 17β‐hydroxysteroid dehydrogenase type 2 21.04.2016 Bern, Switzerland Odermatt Alexander;
Weiterbildungstag der Silamed: Hormone von der Konzeption bis zur Pensionierung Talk given at a conference Hormonaktive Chemikalien in unserer Umwelt 19.04.2016 Horgen, Switzerland Odermatt Alexander;
Congress on Steroid Research Poster Inhibition of 11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole 16.11.2015 Chicago, United States of America Klusonova Petra; Beck Katharina; Odermatt Alexander;
Congress on Steroid Research Talk given at a conference A role for the dehydrogenase DHRS7 (SDR34C1) in prostate cancer 16.11.2015 Chicago, United States of America Odermatt Alexander;
Congress on Steroid Research Poster Biochemical analyses and molecular modeling explain the functional loss of 17β-hydroxysteroid dehydrogenase 3 mutant G133R in three Tunisian patients 16.11.2015 Chicago, United States of America Odermatt Alexander;
17th European Congress of Endocrinology Talk given at a conference 11β-hydroxysteroid dehydrogenase type 1: substrate promiscuity, implications for local glucocorticoid activation? 17.05.2015 Dublin, Ireland Odermatt Alexander;
17th European Congress of Endocrinology Poster Biochemical and molecular modeling analyses explain the functional loss of HSD17B3 mutant G133R in three Tunisian patients 17.05.2015 Dublin, Ireland Odermatt Alexander;
17th European Congress of Endocrinology Poster Determination of the topology of microsomal 17β-hydroxysteroid dehydrogenase enzymes using Redox-sensitive green-fluorescence protein fusions 17.05.2015 Dublin, Ireland Odermatt Alexander;


Self-organised

Title Date Place
Annual Meeting Swiss Society of Toxicology 2016, day on kidney toxicity biomarkers 17.11.2016 Basel, Switzerland
Plenary Session 5: Steroids and Metabolism control. Session Chair 17.11.2015 Chicago, United States of America

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions University Info Day, Pharmacy/Toxicology German-speaking Switzerland 2018
Talks/events/exhibitions University Info Day, Pharmacy/Toxicology German-speaking Switzerland 2017

Awards

Title Year
Poster Preis, Annual Meeting of the Swiss Society of Toxicology 2017

Associated projects

Number Title Start Funding scheme
140961 Generation and Utilization of NADPH in the Endoplasmic Reticulum: Impact on Metabolic and Hormonal Regulation 01.05.2012 Project funding
179400 Impact of the NADPH pool in the endoplasmic reticulum on metabolic and hormonal regulation 01.05.2018 Project funding
179400 Impact of the NADPH pool in the endoplasmic reticulum on metabolic and hormonal regulation 01.05.2018 Project funding

Abstract

An impaired redox control in the endoplasmic reticulum (ER) with unfolded-protein response (UPR) and ER-stress has been associated with major cardio-metabolic diseases, chronic inflammatory disorders and cancer. Thus, it is crucial to elucidate the mechanisms underlying ER-redox control and identify the affected biological reactions. The NAD(P)+/NAD(P)H redox couple plays an essential role in many biological functions. In contrast to the cytoplasm, the role of the NAD(P)+/NAD(P)H redox couple in the ER and the relevance of luminal NADPH for essential biological functions is insufficiently studied. The discovery of hexose-6-phosphate dehydrogenase (H6PDH) revealed a mechanism for NADPH generation in the ER and provided a link between energy status and glucocorticoid signaling. The glucocorticoid activating 11beta-hydroxysteroid dehydrogenase 1 (11b-HSD1) is, so far, the only well characterized NADPH-dependent luminal enzyme. However, the impact of H6PDH on macrophage function and inflammatory mediators and its effect on corticosteroid signaling remain unknown. Also, there must be other NADPH-dependent enzymes because 11b-HSD1 cannot account for the myopathy and the increased susceptibility of hepatocytes observed in situations of H6PDH-deficiency. Based on previous results, we hypothesize that 1) NADPH-dependent 11b-HSD1 function (glucocorticoid-dependent and -independent) essentially modulates macrophage polarization and activity, and inhibition of 11b-HSD1 exerts anti-inflammatory and anti-infective effects, 2) inhibition of 11b-HSD1 has glucocorticoid-independent metabolic effects by modulating oxysterol and bile acid homeostasis, and 3) ER-luminal short-chain dehydrogenase/reductase (SDR) enzymes other than 11b-HSD1 are responsible for effects in macrophage, adipocytes, adrenal cells, hepatocytes and myocytes in situations of H6PDH-deficiency. Therefore, we propose to investigate the consequences of NADPH depletion in the ER on hormonal and metabolic functions and to characterize enzymatic reactions that are dependent on ER luminal NADPH. Specifically, we propose to:•investigate the role of luminal NADPH supply on macrophage polarization and function. We will distinguish between 11b-HSD1-dependent and -independent effects.•assess a potential role of 11b-HSD1 in the metabolism of EBI-2 ligands•elucidate the impact of luminal NADPH supply and 11b-HSD1 on the metabolism of 7-ketocholesterol (7KC) and on bile acid homeostasis•establish a method using redox-sensitive green-fluorescent proteins (roGFP) to determine the topology of ER membrane proteins in living cells and attempt to identify ER luminal enzymes other than 11b-HSD1•characterize the NADPH-dependence of identified luminal enzymes•develop a strategy to identify novel substrates of SDR enzymesThe role of ER luminal NADPH and the consequences of its depletion on metabolic and hormonal responses will be studied in transfected cells using recombinant enzymes, in cell lines with endogenous expression of the relevant enzymes and treated with siRNA, in primary cells from wild-type and H6PDH knockout mice, and in vivo in wild-type and transgenic mice. Structural modeling will be applied in a search for novel SDR substrates and to further study experimentally verified target-ligand interactions. The proposed research should significantly enhance our current knowledge on the role of NADPH in the ER. The expected findings are relevant regarding the understanding of the coupling between cellular energy state, hormonal regulation, ER redox regulation, and oxidative stress-induced damage. Disturbed functions of the enzymes investigated are associated with impaired inflammatory responses and with cardio-metabolic disorders, and the results of the proposed project should support the future development of therapeutic interventions.
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