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1. Changes in circulating miRNA19a-3p precede insulin resistance programmed by intra-uterine growth retardation in mice

Author

Saget, Sarah, Cong, Rong, Decourtye, Lyvianne, Endale, Marie-Laure, Martinerie, Laetitia, Girardet, Clémence, Perret, Claire, Clemessy, Maud, Leneuve, Patricia, Dinard, Laetitia, Mohand Oumoussa, Badreddine, Farabos, Dominique, Lamazière, Antonin, Lombès, Marc, Moldes, Marthe, Fève, Bruno, Tregouet, David, Le Bouc, Yves, and Kappeler, Laurent

Published
2020
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7. FRI163 Central Role Of Mirnas During Kidney Development And Establishment Of The Mineralocorticoid Signaling Pathway Establishment Of The Mineralocorticoid Signaling Pathway

Author

Hani, Imene, primary, An Vu, Thi, additional, Brillet, Riwan, additional, Perrot, Julie, additional, Bouligand, Jérôme, additional, Guegan, Justine, additional, Cherradi, Nadia, additional, Kamenicky, Peter, additional, Lombes, Marc, additional, Martinerie, Laetitia, additional, and Viengchareun, Say, additional

Published
2023
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11. Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease

Author

Ciolek, Justyna, Reinfrank, Helen, Quinton, Loïc, Viengchareun, Say, Stura, Enrico A., Vera, Laura, Sigismeau, Sabrina, Mouillac, Bernard, Orcel, Hélène, Peigneur, Steve, Tytgat, Jan, Droctové, Laura, Beau, Fabrice, Nevoux, Jerome, Lombès, Marc, Mourier, Gilles, De Pauw, Edwin, Servent, Denis, Mendre, Christiane, Witzgall, Ralph, and Gilles, Nicolas

Published
2017

12. Decreased expression of the glucocorticoid receptor-GILZ pathway in Kupffer cells promotes liver inflammation in obese mice

Author

Robert, Olivier, Boujedidi, Hédia, Bigorgne, Amélie, Ferrere, Gladys, Voican, Cosmin Sebastian, Vettorazzi, Sabine, Tuckermann, Jan Peter, Bouchet-Delbos, Laurence, Tran, Thi, Hemon, Patrice, Puchois, Virginie, Dagher, Ibrahim, Douard, Richard, Gaudin, Francoise, Gary-Gouy, Hélène, Capel, Francis, Durand-Gasselin, Ingrid, Prévot, Sophie, Rousset, Sophie, Naveau, Sylvie, Godot, Véronique, Emilie, Dominique, Lombès, Marc, Perlemuter, Gabriel, and Cassard, Anne-Marie

Published
2016
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14. Germline and somatic genetic variations of TNFAIP3 in lymphoma complicating primary Sjögren's syndrome

Author

Nocturne, Gaetane, Boudaoud, Saida, Miceli-Richard, Corinne, Viengchareun, Say, Lazure, Thierry, Nititham, Joanne, Taylor, Kimberly E., Ma, Averil, Busato, Florence, Melki, Judith, Lessard, Christopher J., Sivils, Kathy L., Dubost, Jean-Jacques, Hachulla, Eric, Gottenberg, Jacques Eric, Lombès, Marc, Tost, Jorg, Criswell, Lindsey A., and Mariette, Xavier

Published
2013
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16. Progesterone receptor isoform ratio dictates antiprogestin/progestin effects on breast cancer growth and metastases: A role for NDRG1

Author

Abascal, María Florencia, primary, Elía, Andrés, additional, Alvarez, Michelle, additional, Pataccini, Gabriela, additional, Sequeira, Gonzalo, additional, Riggio, Marina, additional, Figueroa, Virginia, additional, Lamb, Caroline A., additional, Rojas, Paola A., additional, Spengler, Eunice, additional, Martínez‐Vazquez, Paula, additional, Burruchaga, Javier, additional, Liguori, Marcos, additional, Sahores, Ana, additional, Wargon, Victoria, additional, Molinolo, Alfredo, additional, Hewitt, Stephen, additional, Lombes, Marc, additional, Sartorius, Carol, additional, Vanzulli, Silvia Inés, additional, Giulianelli, Sebastián, additional, and Lanari, Claudia, additional

Published
2021
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18. Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice

Author

Geerling, Janine J., Boon, Mariette R., van der Zon, Gerard C., van den Berg, Sjoerd A.A., van den Hoek, Anita M., Lombes, Marc, Princen, Hans M.G., Havekes, Louis M., Rensen, Patrick C.N., and Guigas, Bruno

Subjects
Metformin -- Dosage and administration -- Physiological aspects, Triglycerides -- Measurement -- Physiological aspects, Brown adipose tissue -- Physiological aspects, Low density lipoproteins -- Physiological aspects, Health
Abstract

Metformin is the first-line drug for the treatment of type 2 diabetes. Besides its well-characterized antihyperglycemic properties, metformin also lowers plasma VLDL triglyceride (TG). In this study, we investigated the underlying mechanisms in APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism. We found that metformin markedly lowered plasma total cholesterol and TG levels, an effect mostly due to a decrease in VLDL-TG, whereas HDL was slightly increased. Strikingly, metformin did not affect hepatic VLDL-TG production, VLDL particle composition, and hepatic lipid composition but selectively enhanced clearance of glycerol tri[³H]oleate-labeled VLDL-like emulsion particles into brown adipose tissue (BAT). BAT mass and lipid droplet content were reduced in metformin-treated mice, pointing to increased BAT activation. In addition, both AMP-activated protein kinase α1 (AMPKα1) expression and activity and HSL and mitochondrial content were increased in BAT. Furthermore, therapeutic concentrations of metformin increased AMPK and HSL activities and promoted lipolysis in T37i differentiated brown adipocytes. Collectively, our results identify BAT as an important player in the TG-lowering effect of metformin by enhancing VLDL-TG uptake, intracellular TG lipolysis, and subsequent mitochondrial fatty acid oxidation. Targeting BAT might therefore be considered as a future therapeutic strategy for the treatment of dyslipidemia. DOI: 10.2337/db13-0194, Metformin is one of the most widely used glucose-lowering agents for the treatment of type 2 diabetes (1) and is now considered the first-line drug therapy for patients (2). This [...]

Published
2014
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19. Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation

Author

Bouligand; Jerome, Ghervan, Cristina, Tello, Javier A., Brailly-Tabard, Sylvie, Salenave, Sylvie, Chanson, Philippe, Lombes, Marc, Millar, Robert P., Guiochon-Mantel, Anne, and Young, Jacques

Subjects
Gene mutations -- Health aspects, Gene mutations -- Research, Hypogonadism -- Causes of
Abstract

The article discusses whether mutations in the gene encoding gonadotropin-releasing hormone 1 (GNRH1) is responsible for causing isolated familial hypogonadotropic hypogonadism (IHH) in humans. No significant effects were found of GNRH1 mutations on IHH in humans, thereby indicating its lack of importance.

Published
2009

20. Involvement of SIK2/TORC2 signaling cascade in the regulation of insulin-induced PGC-1[alpha] and UCP-1 gene expression in brown adipocytes

Author

Muraoka, Masaaki, Fukushima, Aiko, Viengchareun, Say, Lombes, Marc, Kishi, Fukuko, Miyauchi, Akira, Kanematsu, Mariko, Doi, Junko, Kajimura, Junko, Nakai, Ryo, Uebi, Tatsuya, Okamoto, Mitsuhiro, and Takemori, Hiroshi

Subjects
Binding proteins -- Physiological aspects, Binding proteins -- Research, Gene expression -- Research, Cellular signal transduction -- Research, Fat cells -- Genetic aspects, Fat cells -- Physiological aspects, Fat cells -- Research, Biological sciences
Abstract

Salt-inducible kinase 2 (SIK2) is expressed abundantly in adipose tissues and represses cAMP-response element-binding protein (CREB)-mediated gene expression by phosphorylating the coactivator transducer of regulated CREB activity (TORC2). Phosphorylation at [Ser.sup.587] of SIK2 diminishes its TORC2 phosphorylation activity. In 3T3-LI white adipocytes, SIK2 downregulates lipogenic gene in response to nutritional stresses. To investigate the impact of SIK2 on the function of brown adipose tissue (BAT), we used T37i brown adipocytes, mice with diet-induced obesity, and SIK2 mutant (S587A) transgenic mice. When T37i adipocytes were treated with insulin, the levels of peroxisome proliferator-activated receptor-coactivator-l[alpha] (PGC-1[alpha]) and uncoupling protein-1 (UCP-1) mRNA were increased, and the induction was inhibited by overexpression of SIK2 (S587A) mutant or dominant-negative CREB. Insulin enhanced SIK2 phosphorylation at [Ser.sup.587], which was accompanied by decrease in phospho-TORC2. Similarly, the decrease in the level of SIK2 phosphorylation at [Ser.sup.587] was observed in the BAT of mice with diet-induced obesity, which was negatively correlated with TORC2 phosphorylation. To confirm the negative correlation between SIK2 phosphorylation at [Ser.sup.587] and TORC2 phosphorylation in BAT, SIK2 mutant (S587A) was overexpressed in adipose tissues by using the adipocyte fatty acid-binding protein 2 promoter. The expression of recombinant SIK2 (S587A) was restricted to BAT, and the levels of phospho-TORC2 were elevated in BAT of transgenic mice. Male transgenic mice developed high-fat diet-induced obesity, and their BAT expressed low levels of PGC-1[alpha] and UCP-1 mRNA, suggesting that SIK2-TORC2 cascade may be important for the regulation of PGC-1[alpha] and UCP-1 gene expression in insulin signaling in BAT. salt-inducible kinase 2; peroxisome proliferator-activated receptorcoactivator-l[alpha]; uncoupling protein-l; brown adipocyte; adenosine 5',3'-cyclic monophosphate-response element-binding protein

Published
2009

21. Pharmacology of Hormone Replacement Therapy in Menopause

Author

Voican, Adela, primary, Francou, Bruno, additional, Novac, Liliana, additional, Chabbert-Buffet, Nathalie, additional, Canonico, Marianne, additional, Meduri, Geri, additional, Lombes, Marc, additional, Scarabin, Pierre-Yves, additional, Young, Jacques, additional, Guiochon-Mantel, Anne, additional, and Boulig, Jrme, additional

Published
2012
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24. Progesterone receptor isoform ratio dictates antiprogestin/progestin effects on breast cancer growth and metastases: A role for NDRG1.

Author

Abascal, María Florencia, Elia, Andrés, Alvarez, Michelle, Pataccini, Gabriela, Sequeira, Gonzalo, Riggio, Marina, Figueroa, Virginia, Lamb, Caroline A., Rojas, Paola A., Spengler, Eunice, Martínez‐Vazquez, Paula, Burruchaga, Javier, Liguori, Marcos, Sahores, Ana, Wargon, Victoria, Molinolo, Alfredo, Hewitt, Stephen, Lombes, Marc, Sartorius, Carol, and Vanzulli, Silvia Inés

Subjects
PROGESTATIONAL hormones, PROGESTERONE receptors, TUMOR suppressor proteins, LYMPHATIC metastasis, PROGESTERONE antagonists
Abstract

Progesterone receptors (PRs) ligands are being tested in luminal breast cancer. There are mainly two PR isoforms, PRA and PRB, and their ratio (PRA/PRB) may be predictive of antiprogestin response. Our aim was to investigate: the impact of the PR isoform ratio on metastatic behaviour, the PR isoform ratio in paired primary tumours and lymph node metastases (LNM) and, the effect of antiprogestin/progestins on metastatic growth. Using murine and human metastatic models, we demonstrated that tumours with PRB > PRA (PRB‐H) have a higher proliferation index but less metastatic ability than those with PRA > PRB (PRA‐H). Antiprogestins and progestins inhibited metastatic burden in PRA‐H and PRB‐H models, respectively. In breast cancer samples, LNM retained the same PRA/PRB ratio as their matched primary tumours. Moreover, PRA‐H LNM expressed higher total PR levels than the primary tumours. The expression of NDRG1, a metastasis suppressor protein, was higher in PRB‐H compared to PRA‐H tumours and was inversely regulated by antiprogestins/progestins. The binding of the corepressor SMRT at the progesterone responsive elements of the NDRG1 regulatory sequences, together with PRA, impeded its expression in PRA‐H cells. Antiprogestins modulate the interplay between SMRT and AIB1 recruitment in PRA‐H or PRB‐H contexts regulating NDRG1 expression and thus, metastasis. In conclusion, we provide a mechanistic interpretation to explain the differential role of PR isoforms in metastatic growth and highlight the therapeutic benefit of using antiprogestins in PRA‐H tumours. The therapeutic effect of progestins in PRB‐H tumours is suggested. [ABSTRACT FROM AUTHOR]

Published
2022
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25. SAT-LB106 Metabolic and Brown Adipose Tissue-Specific Effects of the Novel Non-Steroidal Mineralocorticoid Receptor Antagonist Finerenone in a Mouse Model of Diet-Induced Obesity

Author

Marzolla, Vincenzo, primary, Feraco, Alessandra, primary, Gorini, Stefania, primary, Mammi, Caterina, primary, Marrese, Carmen, primary, Boitani, Carla, primary, Lombes, Marc, primary, Kolkhof, Peter, primary, Ciriolo, Maria Rosa, primary, Armani, Andrea, primary, and Caprio, Massimiliano, primary

Published
2020
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30. Aldosterone-induced apical Na+ and K+ conductances are located predominantly in surface cells in rat distal colon

Author

Lomax, Richard B., McNicholas, Carmel M., Lombes, Marc, and Sandle, Geoffrey I.

Subjects
Aldosterone -- Analysis, Colon (Anatomy) -- Analysis, Rats -- Research, Biological sciences
Abstract

Surface cell population in rat distal colon and smaller scale crypt cells with aldosterone receptors contain aldosterone-induced Na+ and Ka+ conductances. Differing phases of differentiation along the surface cell crypt cells axis are evident from this range of aldosterone-induced Na+ and K+ conductances. Site-directed intracellular microelectrodes, specific Na+ and K+ channel blockers and aldosterone receptor binding methods facilitate the analysis of the distribution of aldosterone-sensitive cell types in this region.

Published
1994

32. Thyroid hormones are new key regulators of glucocorticoid metabolism

Author

Bessiene, Laura, primary, Hescot, Segolene, additional, Bourdin-Pintueles, Alexandra, additional, Dumeige, Laurence, additional, Vitellius, Geraldine, additional, Perrot, Julie, additional, Xu, Qiong-Yao, additional, Vu, Thi-An, additional, Sachs, Laurent, additional, Pussard, Eric, additional, Lombes, Marc, additional, Viengchareun, Say, additional, and Martinerie, Laetitia, additional

Published
2019
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35. Molecular events in a large series of advanced stage III-IV adrenocortical cancer: looking for new therapeutic options

Author

De, Martino Maria Cristina, primary, Lacroix, Ludovic, additional, Aubert, Sebastien, additional, Libe, Rossella, additional, Al, Ghuzlan Abir, additional, de, la Fouchardiere Christelle, additional, Hescot, Segolene, additional, Assie, Guillaume, additional, Honore, Aurelie, additional, Deschamps, Fred, additional, Lombes, Marc, additional, Borson-Chazot, Francoise, additional, Pattou, Francois, additional, Pivonello, Rosario, additional, Borget, Isabelle, additional, Schlumberger, Martin, additional, Leboulleux, Sophie, additional, Scoazec, Jean-Yves, additional, Bertherat, Jerome, additional, Cao, Christine Do, additional, and Baudin, Eric, additional

Published
2019
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40. OR10-1 Regulation of Glucocorticoid Metabolism: A Novel Function for Thyroid Hormones?

Author

Bessiene, Laura, primary, Hescot, Segolene, additional, Bourdin-Pintueles, Alexandra, additional, Dumeige, Laurence, additional, Vitellius, Géraldine, additional, Perrot, Julie, additional, Xu, Qing-Yao, additional, Vu, Thi An, additional, Sachs, Laurent, additional, Pussard, Eric, additional, Lombes, Marc, additional, Viengchareun, Say, additional, and Martinerie, Laetitia, additional

Published
2019
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43. Identifying mitotane-induced mitochondria-associated membranes dysfunctions : metabolomic and lipidomic approaches

Author

Hescot, Segolene, Amazit, Larbi, Lhomme, Marie, Travers, Simon, Dubow, Anais, Battini, Stephanie, Boulate, Geoffrey, Namer, Izzie Jacques, Lombes, Anne, Kontush, Anatol, Imperiale, Alessio, Baudin, Eric, Lombes, Marc, Bos, Mireille, Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Biomédical de Bicêtre (US 32), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Service de Biophysique et Médecine Nucléaire, CHU Strasbourg-Université Louis Pasteur - Strasbourg I-Hôpital de Hautepierre [Strasbourg], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'endocrinologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Institut Biomédical de Bicêtre ( US 32 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie ( ICube ), Institut National des Sciences Appliquées - Strasbourg ( INSA Strasbourg ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg ( ENGEES ) -Réseau nanophotonique et optique, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Centre National de la Recherche Scientifique ( CNRS ) -Matériaux et nanosciences d'Alsace, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Groupe hospitalier Pitié- Salpêtrière, AP-HP, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
mitotane, mitochondria-associated membranes, adrenocortical carcinoma, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, lipidomics, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, molecular target
Abstract

International audience; Mitotane (o,p'DDD), the most effective drug in adrenocortical carcinoma, concentrates into the mitochondria and impacts mitochondrial functions. To address the molecular mechanisms of mitotane action and to identify its potential target, metabolomic and lipidomic approaches as well as imaging analyses were employed in human adrenocortical H295R cells allowing identification of Mitochondria-Associated Membranes dysfunction as a critical impact of mitotane. Study of intracellular energetic metabolites by NMR spectroscopy showed that mitotane significantly decreased aspartate while concomitantly increased glutamate content in a time-and concentration-dependent manner. Such alterations were very likely linked to the previously described, mitotane-induced respiratory chain defect. Lipidomic studies of intracellular and intramitochondrial phospholipids revealed that mitotane exposure markedly reduced the phosphatidylserine/phosphatidylethanolamine ratio, indicative of a dysfunction of phosphatidylserine decarboxylase located in Mitochondria-Associated Membranes. Expression levels of Mitochondria-Associated Membranes proteins phosphatidylserine decarboxylase, DRP1, ATAD3A or TSPO were greatly reduced by mitotane as assessed by western blot analyses. Mitotane exposure markedly altered endogenous Mitochondria-Associated Membranes integrity and reduced the magnitude of mitochondria and the endoplasmic reticulum interactions as demonstrated by high resolution deconvolution microscopy and quantification. Finally, we showed that PK11195, a pharmacological inhibitor of the cholesterol translocator TSPO, embedded in Mitochondria-Associated Membranes, exerts a synergetic effect with mitotane in inducing Mitochondria-Associated Membranes disruption, apoptosis and in inhibiting steroid secretion. Altogether, our results demonstrate Mitochondria-Associated Membranes dysfunction in H295R cells treated with mitotane and that TSPO inhibition significantly potentiates mitotane antitumoral and antisecretory actions in vitro. This constitutes a potential and promising pharmacological strategy for patients with adrenocortical carcinoma.

Published
2017
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44. Cistrome of the Aldosterone-activated Mineralocorticoid Receptor in Human Renal Cells

Author

Le Billan, Florian, Khan, Junaid Ali, Lamribet, Kadhija, Viengchareun, Say, Bouligand, Jérôme, Fagart, Jérome, Lombes, Marc, and Lombes, Marc

Subjects
[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Sodium, Chromatin Immunoprecipitation sequencing, Kidney, Mineralocorticoid Receptor Target Genes, Aldosterone
Abstract

Aldosterone acts mainly by activating the mineralocorticoid receptor (MR), a transcription factor that regulates gene expression through complex and dynamic interactions with coregulators and transcriptional machinery, leading to fine-tuned control of vectorial ionic transport in the distal nephron. To identify genome-wide aldosterone-regulated MR targets in human renal cells, we set up the chromatin immunoprecipitation (ChIP) using a specific anti-MR antibody in a differentiated human renal cell line expressing GFP-MR. This approach coupled with high-throughput sequencing allowed identification of 974 genomic MR targets. Computational analysis identified a MR response element (MRE) including single or multiple half-sites and palindromic motifs in which the AGtACAgxatGTtCt sequence was the most prevalent motif. Most genomic MR binding sites (MBS) are located at distance >10 Kb from the transcriptional start sites of target genes (84%). Specific aldosterone-induced recruitment of MR on the first most relevant genomic sequences was further validated by ChIP-qPCR and correlated with concomitant and positive aldosterone-activated transcriptional regulation of the corresponding gene as assayed by RT-qPCR. Interestingly, most MBS lack MRE but harbor DNA recognition motifs for other transcription factors (FOX, EGR1, AP1, PAX5) suggesting functional interaction. This work provides new insights into aldosterone, MR-mediated renal signaling and opens relevant perspectives for mineralocorticoid-related pathophysiology.

Published
2015

45. Glucocorticoid resistance syndrome.

Author

Vitellius, Géraldine and Lombes, Marc

Subjects
*GLUCOCORTICOIDS, *RENIN-angiotensin system, *CUSHING'S syndrome, *GLUCOCORTICOID receptors, *ADRENAL insufficiency, *LIGAND binding (Biochemistry)
Abstract

Glucocorticoids (GC) such as cortisol regulate multiple physiol ogical functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert their e ffects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene in humans). GC signaling follows several consecutive step s leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, and recruitment of functional transcriptional machinery. Generalized glucocorticoid resistance syndrome, due to GR loss-of-function mutations, may be related to the impairment of one of the GC signaling steps. To date, 31 NR3C1 loss-of-function mutations have been reported in patients prese nting with various clinical signs such as hypertension, adrenal hyperplasia, hirsutism or metabolic disorders associated with biological hypercortisolism but without Cushing syndrome signs and no negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Functional characterization of GR loss-of-function mutations often demonstrates GR haploinsufficiency and a decrease of GR target gene induction in relevant cell types. The main signs at presentation are very variable from resistant hypertension, bilateral adrenal hyperplasia likely related to i ncreased ACTH levels but not exclusively, hirsutism to isolated renin-angiotensin-aldosterone system abnormalities in a context of 11ßHSD2 deficiency. Some mutated GR patients are obese or overweight together with a healthier meta bolic profile that remains to be further explored in future studies. Deciphering the molecular mechanisms altered by GR mutations should enhance our knowledge on GR signaling and ultimately facilitate management of GC-resista nt patients. This review also focuses on the criteria facilitating identification of novel NR3C1 mutations in selected patients. Correspondence. [ABSTRACT FROM AUTHOR]

Published
2020
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46. Significant prevalence of NR3C1 mutations in incidentally discovered bilateral adrenal hyperplasia: results of the French MUTA-GR Study

Author

Vitellius, Géraldine, primary, Trabado, Séverine, additional, Hoeffel, Christine, additional, Bouligand, Jérôme, additional, Bennet, Antoine, additional, Castinetti, Frederic, additional, Decoudier, Bénédicte, additional, Guiochon-Mantel, Anne, additional, Lombes, Marc, additional, Delemer, Brigitte, additional, _, _, additional, Amiot-Chapoutot, F, additional, Ancelle, D, additional, Bertoin, F, additional, Brue, T, additional, Caron, P, additional, Borson-Chazot, F, additional, Christin-Maitre, S, additional, Chabre, O, additional, Dessailloud, R, additional, Estour, B, additional, Grulet, H, additional, Illouz, F, additional, Jeandidier, N, additional, Kerlan, V, additional, Klein, M, additional, Penfornis, A, additional, Pierre, P, additional, Tabarin, A, additional, Touraine, P, additional, Vantyghem, M C, additional, and Young, J, additional

Published
2018
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47. Switch in FGFR 3 and 4 expression profile during human renal development may account for transient hypercalcemia in patients with Sotos syndrome due to 5q35 microdeletions.: Ontogeny of FGFR 3 and 4 in human kidney

Author

Mutsaers, Henricus, Levtchenko, Elena, Martinerie, Laetitia, Pertijs, Jeanne, Allegaert, Karel, Devriendt, Koenraad, Masereeuw, Rosalinde, Monnens, Leo, Lombes, Marc, Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pharmacology and Toxicology, Radboud University Medical Center [Nijmegen], Department of Pediatrics & Department of Growth and Regeneration, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-University Hospitals Leuven [Leuven], departement of Pharmacology, Radboud University, Radboud University Medical Center [Nijmegen]-Radboud University Medical Center [Nijmegen], Centre for Human Genetics, Department of Physiology, PremUp Foundation, Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Renal Association - European Dialysis and Transplant Association (ERA-EDTA, Fellowship no. ERA STF 132-2013, Grant Agreement 1801110N and 1800214N, respectively)., and Lombes, Marc

Subjects
musculoskeletal diseases, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
Abstract

International audience; : Context: Sotos syndrome is a rare genetic disorder with a distinct phenotypic spectrum including overgrowth and learning difficulties. Here we describe a new case of Sotos syndrome with a 5q35 microdeletion, affecting the fibroblast growth factor receptor 4 (FGFR4) gene, presenting with infantile hypercalcemia. Objective: We strived to elucidate the evanescent nature of the observed hypercalcemia by studying the ontogenesis of FGFR3 and FGFR4 - which are both associated with FGF23-mediated mineral homeostasis - in the developing human kidney. Design: RT-qPCR and immunohistochemical analyses were used on archival human kidney samples to investigate expression of the FGFR signaling pathway during renal development. Results: We demonstrated that renal gene and protein expression of both FGFRs increased during fetal development between the gestational ages (GA) of 14-40 weeks. Yet, FGFR4 expression increased more rapidly as compared to FGFR3 (slope: 0.047 vs. 0.0075, p = 0.0018). Moreover, gene and protein expression of the essential FGFR co-receptor, Klotho, also increased with a significant positive correlation between FGFR and Klotho mRNA expression during renal development. Interestingly, we found that perinatal FGFR4 expression (GA 38-40 weeks) was 7-fold higher as compared to FGFR3 (p=0.0035), while in adult kidney tissues, FGFR4 gene expression level was more than 2-fold lower compared to FGFR3 (p=0.0029), thus identifying a molecular developmental switch of FGFR isoforms. Conclusion: We propose that the heterozygous FGFR4 deletion, as observed in the Sotos syndrome patient, leads to a compromised FGF23 signaling during infancy accounting for transient hypercalcemia. These findings represent a novel and intriguing view on FGF23-mediated calcium homeostasis.

Published
2014
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48. Ligand-dependent stabilization of androgen receptor in a novel mouse ST38c Sertoli cell line

Author

Vija, Lavinia, Boukari, Kahina, Loosfelt, Hugues, Meduri, Géri, Viengchareun, Say, Binart, Nadine, Young, Jacques, Lombes, Marc, Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Biophysics and Cellular Bioechnologies, University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), Service d'endocrinologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, This work was supported by fundings from INSERM, Université Paris-Sud. LV was supported by student fellowship from French government, Université Paris Sud and the Alfred Jost fellowship Merck-Serono Pharma, France., and Lombes, Marc

Subjects
[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Androgen receptor, Sertoli cells, ST38c cells, testis, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
Abstract

Mature Sertoli cells (SC) are critical mediators of androgen regulation of spermatogenesis, via the androgen receptor (AR) signaling. Available immortalized SC lines loose AR expression or androgen responsiveness, hampering the study of endogenous AR regulation in SC. We have established and characterized a novel clonal mouse immortalized SC line, ST38c. These cells express some SC specific genes (sox9, wt1, tjp1, clu, abp, inhbb), but not fshr, yet more importantly, maintain substantial expression of endogenous AR as determined by PCR, immunocytochemistry, testosterone binding assays and Western blots. Microarrays allowed identification of some (146) but not all (rhox5, spinlw1), androgen-dependent, SC expressed target genes. Quantitative Real-Time PCR validated regulation of five up-regulated and two down-regulated genes. We show that AR undergoes androgen-dependent transcriptional activation as well as agonist-dependent posttranslational stabilization in ST38c cells. This cell line constitutes a useful experimental tool for future investigations on the molecular and cellular mechanisms of androgen receptor signaling in SC function.

Published
2014

49. Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells

Author

Hescot, Ségolène, Slama, Abdelhamid, Lombes, Anne, Paci, Angelo, Remy, Hervé, Leboulleux, Sophie, Chadarevian, Rita, Trabado, Séverine, Amazit, Larbi, Young, Jacques, Baudin, Eric, Lombes, Marc, Lombes, Marc, Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie [Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Laboratoire HRA-Pharma (HRA), HRA Pharma France, Service de génétique moléculaire, pharmacogénétique et hormonologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service d'endocrinologie, Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), and This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine Paris-Sud, and a grant from HRA Pharma Laboratories. SH was recipient of a fellowship from the French Endocrine Society (SFE, Société Française d'Endocrinologie).

Subjects
mitotane, mitochondria, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Adrenocortical carcinoma, cytochrome c oxidase, p'-DDD, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
Abstract

Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane (o,p'-DDD) is the most effective medical therapy for adrenocortical carcinoma but its molecular mechanism of action remains poorly understood. Although mitotane is known to have mitochondrial (mt) effects, a direct link to mitochondrial dysfunction has never been established. We examined the functional consequences on proliferation, steroidogenesis, and mitochondrial respiratory chain, biogenesis and morphology, of mitotane exposure in two human adrenocortical cell lines, the steroid-secreting H295R line and the non-secreting SW13 line. Mitotane inhibited cell proliferation in a dose- and a time-dependent manner. At the concentration 50μM (14 mg/L), which corresponds to the threshold for therapeutic efficacy, mitotane drastically reduced cortisol and 17-hydroxyprogesterone secretions by 70%. This was accompanied by significant decreases in the expression of genes encoding mitochondrial proteins involved in steroidogenesis (STAR, CYP11B1, CYP11B2). In both H295R and SW13 cells, 50μM mitotane significantly inhibited (50%) the maximum velocity of the activity of the respiratory chain complex IV (cytochrome c oxidase, COX). This effect was associated with a drastic reduction in steady-state levels of the whole COX complex as revealed by Blue Native PAGE and reduced mRNA expression of both mtDNA-encoded COX2 and nuclear DNA-encoded COX4 subunits. In contrast, the activity and expression of respiratory chain complexes II and III were unaffected by mitotane treatment. Lastly, mitotane exposure enhanced mitochondrial biogenesis (increase in mtDNA content and PGC1α expression) and triggered fragmentation of the mitochondrial network. Altogether, our results provide first evidence that mitotane induced a mitochondrial respiratory chain defect in human adrenocortical cells.

Published
2014

50. Hypertonicity compromises renal mineralocorticoid receptor signaling through Tis11b-mediated posttranscriptional control

Author

Viengchareun, Say, Lema, Ingrid, Lamribet, Kadhija, Keo, Vixra, Blanchard, Anne, Cherradi, Nadia, Lombes, Marc, Lombes, Marc, Récepteurs stéroïdiens : physiopathologie endocrinienne et métabolique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'endocrinologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, This work was supported by grants from Inserm, Université Paris-Sud and Agence Nationale de la Recherche (ANR 11-BSV1-028-01). IL is recipient of a CORDDIM fellowship., and ANR EPHIMIR

Subjects
[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
Abstract

The Mineralocorticoid Receptor (MR) mediates Na+-retaining action of aldosterone. It is highly expressed in the distal nephron which is submitted to intense variations of the extracellular fluid tonicity generated by the corticopapillary gradient. We previously showed that posttranscriptional events control renal MR abundance. Here, we find that hypertonicity increases expression of the mRNA-destabilizing protein Tis11b, a member of tristetraprolin/ZFP36 family, and thereby decreases MR expression in renal KC3AC1 cells. The 3'-Untranslated region (3'-UTR) of human and mouse MR mRNA containing several highly conserved Adenylate/Uridylate-Rich Elements (ARE), were cloned downstream of a reporter gene. Luciferase activities of full length or truncated Luc-3'-UTR mutants were drastically reduced when cotransfected with Tis11b plasmid in HEK293T cells, consistent with a 50% shorter half-life of ARE-containing transcripts. We identified a crucial ARE motif within MR 3'-UTR, to which Tis11b binds as shown by site-directed mutagenesis and RNA Immunoprecipitation, responsible for Tis11b-mediated destabilizing activity. Importantly, endogenous Tis11b physically interacts with MR mRNA in KC3AC1 cells, leading to hypertonicity-elicited MR repression as demonstrated by Tis11b knockdown. Moreover, hypertonicity impaired MR signaling by blunting aldosterone-stimulated Gilz and αENaC expression in the Na+-transporting KC3AC1 cells. Challenging the renal osmotic gradient by submitting mice to water deprivation, diuretic administration or high Na+ diet increased renal Tis11b while decreased MR expression, notably in the cortex, thus establishing a mechanistic pathway for osmotic regulation of MR expression in vivo. Altogether, we uncover a previously undetected mechanism by which renal MR expression is regulated via mRNA turnover, a posttranscriptional control which appears physiologically relevant.

Published
2014

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