ECE2019 Oral Communications Endocrine Connections 1 (5 abstracts)
Thyroid hormones are new key regulators of glucocorticoid metabolism
Laura Bessiène 1 , Ségolène Hescot 2 , Alexandra Bourdin-Pintueles 2 , Laurence Dumeige 2 , Géraldine Vitellius 2 , Julie Perrot 2 , Qiong-Yao Xu 2 , Thi-An Vu 2 , Laurent Sachs 3 , Eric Pussard 4 , Marc Lombès 2 , Say Viengchareun 2 & Laetitia Martinerie 2,
1Inserm U1185, Paris-Sud Medical School, Paris-Saclay University, Le Kremlin-Bicêtre, France; 2Inserm U1185, Paris-Sud Medical School, Paris-Saclay University, Le Kremlin- Bicêtre, France; 3UMR 7221 CNRS - Muséum National d’Histoire NaturelleUMR 7221 CNRS - Muséum National d’Histoire Naturelle, Paris, France; 4Department of Molecular Genetics, Pharmacogenetics, Hormonology, Paris-Sud University Hopitaux, Le Kremlin- Bicêtre, France; 5Department of Pediatric Endocrinology, Robert Debré Hospital, Paris, France.
The 11-beta hydroxysteroid dehydrogenase (11βHSD) isozymes are well-known regulators of glucocorticoid hormone metabolism: 11βHSD2, mostly expressed in the distal nephron, converts cortisol [F] into cortisone [E] in humans or corticosterone into 11-dehydrocorticosterone in rodents (11-dehydro derivatives being inactive compounds), and 11βHSD1, ubiquitously expressed but predominantly in the liver, catalyzes the opposite reaction. Under pathophysiological conditions of hypothyroidism in humans, altered glucocorticoid metabolism has been observed, with decreased [F] to [E] conversion (Boonen, NEJM, 2013; Warner, J Endocrinol, 2010). However, direct functional relationship between these two hormonal pathways has never been demonstrated to date. Using bioinformatics analyses, we identified five putative thyroid hormone response elements in the murine promoter region of the hsd11b2 gene. Therefore, we aimed at investigating whether thyroid hormones (T3) directly regulate expression and/or activity of the 11βHSD2 enzyme. We used three complementary models: human and mouse translational studies and molecular analyses in HEK293T cells and in fully differentiated KC3AC1 cortical collecting duct cells. Children and adults with hypo- or hyperthyroidism were compared either to age- and sex-matched euthyroid controls, or to themselves after reaching an euthyroid status. The urinary [E]/[F] ratio measured by LC-MS/MS method, was used as an index of renal 11βHSD2 activity. Interestingly, a 60% decrease (P<0.05) in the [E]/[F] ratio was observed in hypothyroid patients, suggesting a regulation of glucocorticoid metabolism by thyroid hormones. Next, a mouse model of hyperthyroidism, generated by administrating T3 in drinking water, led to a significant 10% increase in renal 11βHSD2 mRNA and protein levels compared to wild type mice (n=20, P<0.05). We also demonstrated in HEK293T cells that T3 transactivates both the mouse hsd11b2 and human HSD11B2 promoter cloned upstream of the luciferase reporter gene via the Thyroid Receptor α1 (TRα1) and that transactivations are abolished in the presence of the NH3 antagonist. Finally, we showed that T3 exposure induces a 50% increase in 11βHSD2 mRNA levels in renal KC3AC1 cells, in a dose-dependent and time-dependent manner (P<0.01). Actinomycin D also blunted this effect, underlining a direct transcriptional regulatory mechanism. In addition, 11βHSD2 enzymatic activity, quantified by the [F] to [E] conversion ratio measured by LC-MS/MS in cell supernatants, increased significantly by 20% (P<0.05) after 24 h exposure to 100 nM T3. ChIP experiments further demonstrated a T3-dependent specific recruitment of TRα1 onto hsd11b2 promoter region. Altogether, our findings demonstrate that thyroid hormones directly regulate expression and activity of the renal 11βHSD2 enzyme, thereby controlling glucocorticoid metabolism and action.
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more