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The regulation of glucocorticoid and mineralocorticoid hormone action by 11beta-hydroxysteroid dehydrogenases
English title
The regulation of glucocorticoid and mineralocorticoid hormone action by 11beta-hydroxysteroid dehydrogenases
Applicant
Odermatt Alexander
Number
112279
Funding scheme
Project funding
Research institution
Universität Basel
Institution of higher education
University of Basel - BS
Main discipline
Biochemistry
Start/End
01.05.2006 - 30.04.2009
Approved amount
377'000.00
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All Disciplines (2)
Discipline
Biochemistry
Molecular Biology
Keywords (11)
cortisone; cortisol; aldosterone; 11beta-hydroxysteroid dehydrogenase; kidney; hypertension; mineralocorticoid; glucocorticoid; steroid metabolism; metabolic disease; inhibitor
Lay Summary (English)
Lead
Lay summary
We studied intracellular corticosteroid control and effects of inappropriate regulation of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR), relevant for diseases such as hypertension, inflammation, obesity and diabetes. A tight control of corticosteroid homeostasis is essential. Disturbances have been associated with metabolic syndrome, osteoporosis, infection, cataract and cardiovascular disease. Glucocorticoid and mineralocorticoid action is tissue-specifically regulated by 11beta-hydroxysteroid dehydrogenases (11HSDs). 11HSD1 converts inactive (cortisone, 11-dehydrocorticosterone) to active glucocorticoids (cortisol, corticosterone). Due to elevated expression in obese individuals and association with metabolic syndrome, 11HSD1 has emerged as a promising therapeutic target. 11HSD2 catalyzes the reverse reaction and prevents cortisol-induced MR activation. Clinical trials revealed reduced mortality in patients with heart failure on treatment with MR antagonists.We identified a novel mutation in 11HSD2 of a patient with inherited hypertension. The mutation led to a single amino acid substitution and resulted in a protein with normal kinetic properties but a six-fold shorter half-life. Impaired 11HSD2 protein stability leads to insufficient cortisol inactivation and MR activation, explaining the severe hypertension of this patient.Impaired tissue-specific glucocorticoid regulation can also be due to altered transcriptional expression of 11HSDs. We studied the impact of nutrients and endogenous hormones on 11HSD expression and found that dehydroepiandrosterone downregulated 11HSD1 in liver and adipose tissue and increased 11HSD2 in the kidney. The major vitamin A metabolite retinoic acid decreased 11HSD1 activity in skeletal muscle cells and adipocytes and induced 11HSD2 in a kidney cell line. This suggests that nutrients and endogenous hormones modulate tissue-specific glucocorticoid metabolism and that they counteract effects of pro-inflammatory cytokines. 11HSD1 is a reversible enzyme. Its ability to activate glucocorticoids depends on the availability of cosubstrate NADPH. We demonstrated a direct interaction of 11HSD1 with the enzyme hexose-6-phosphate dehydrogenase (H6PDH) that generates cosubstrate NADPH in the endoplasmic reticulum. Further, we showed that 11HSD1 activity depends on glucose availability. Thus, redox potential in the endoplasmic reticulum and energy status modulate local glucocorticoid responses, representing another level of cell-specific glucocorticoid regulation. Our findings deepen the understanding of corticosteroid action and are relevant for the development of therapeutic interventions.
Direct link to Lay Summary
Last update: 21.02.2013
Responsible applicant and co-applicants
Name
Institute
Odermatt Alexander
Abteilung Molekular- und Systemtoxikologie Departement Pharmazeutische Wissenschaften Universität Basel
Employees
Name
Institute
Atanasov Atanas G.
Respiratory Medicine Department Universitätsklinik Inselspital
Dzyakanchuk Hanna
Department for BioMedical Research Universität Bern
Nashev Lyubomir Georgiev
Respiratory Medicine Department Universitätsklinik Inselspital
Gumy Christel
Respiratory Medicine Department Universitätsklinik Inselspital
Maurer Evelyne
Respiratory Medicine Department Universitätsklinik Inselspital
Associated projects
Number
Title
Start
Funding scheme
100060
Identification and Characterization of Mechanisms Controlling Intracellular Glucocorticoid Concentrations.
01.05.2003
Project funding
124912
The Regulation of Glucocorticoid and Mineralocorticoid Hormone Action by 11beta-Hydroxysteroid Dehydrogenases
01.05.2009
Project funding
127330
The role of the endoplasmic reticulum in the metabolism of xenobiotics
01.10.2009
ProDoc
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