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1. Procollagen C-Proteinase Enhancer-1 (PCPE-1) deficiency in mice reduces liver fibrosis but not NASH progression.

Author

Patricia Sansilvestri Morel, Valerie Duvivier, Florence Bertin, Nicolas Provost, Adel Hammoutene, Edwige-Ludiwyne Hubert, Arantxa Gonzalez, Isabelle Tupinon-Mathieu, Valerie Paradis, and Philippe Delerive

Subjects
Medicine, Science
Abstract

Background and aimsNonalcoholic Steatohepatitis (NASH) is a major cause of end-stage liver diseases such as cirrhosis and hepatocellular carcinoma resulting ultimately in increased liver-related mortality. Fibrosis is the main driver of mortality in NASH. Procollagen C-Proteinase Enhancer-1 (PCPE-1) plays a key role in procollagen maturation and collagen fibril formation. To assess its role in liver fibrosis and NASH progression, knock-out mice were evaluated in a dietary NASH model.MethodsGlobal constitutive Pcolce-/- and WT male mice were fed with a Choline Deficient Amino acid defined High Fat Diet (CDA HFD) for 8 weeks. Liver triglycerides, steatosis, inflammation and fibrosis were assessed at histological, biochemical and gene expression levels. In addition, human liver samples from control and NASH patients were used to evaluate the expression of PCPE-1 at both mRNA and protein levels.ResultsPcolce gene deficiency prevented diet-induced liver enlargement but not liver dysfunction. Furthermore, liver triglycerides, steatosis and inflammation were not modified in Pcolce-/- male mice compared to WT under CDA HFD. However, a significant decrease in liver fibrosis was observed in Pcolce-/- mice compared to WT under NASH diet, associated with a decrease in total and insoluble collagen content without any significant modifications in the expression of genes involved in fibrosis and extracellular matrix remodeling. Finally, PCPE-1 protein expression was increased in cirrhotic liver samples from both NASH and Hepatitis C patients.ConclusionsPcolce deficiency limits fibrosis but not NASH progression in CDA HFD fed mice.

Published
2022
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2. Type 2 diabetes is associated with impaired jejunal enteroendocrine GLP-1 cell lineage in human obesity

Author

Juan de Toro-Martín, Patricia Serradas, Agnès Ribeiro, Céline Osinski, Laurent Genser, Corinne Blugeon, Armelle Leturque, Laurent Jourdren, Magali Fradet, Edwige Ludiwyne Hubert, Karine Clément, Christine Poitou, Léa Le Gléau, Hédi Soula, Gestionnaire, HAL Sorbonne Université 5, Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut des Nutraceutiques et des Aliments Fonctionnels (INAF), Université Laval [Québec] (ULaval), Service de Chirurgie Digestive, Hépato-Bilio-pancréatique et Transplantation Hépatique [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), GenomiqueENS (Genomique ENS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, Institut de Recherches Internationales Servier [Suresnes] (IRIS), Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Service de nutrition [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Lineage (genetic), Endocrinology, Diabetes and Metabolism, Cellular differentiation, Enteroendocrine Cells, Medicine (miscellaneous), 030209 endocrinology & metabolism, Enteroendocrine cell, Type 2 diabetes, Biology, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Obesity, Cells, Cultured, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Nutrition and Dietetics, Proglucagon, Cell sorting, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, medicine.disease, stomatognathic diseases, 030104 developmental biology, Endocrinology, Jejunum, Diabetes Mellitus, Type 2, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female
Abstract

Objectives Altered enteroendocrine cell (EEC) function in obesity and type 2 diabetes is not fully understood. Understanding the transcriptional program that controls EEC differentiation is important because some EEC types harbor significant therapeutic potential for type 2 diabetes. Methods EEC isolation from jejunum of obese individuals with (ObD) or without (Ob) type 2 diabetes was obtained with a new method of cell sorting. EEC transcriptional profiles were established by RNA-sequencing in a first group of 14 Ob and 13 ObD individuals. EEC lineage and densities were studied in the jejunum of a second independent group of 37 Ob, 21 ObD and 22 non obese (NOb) individuals. Results The RNA seq analysis revealed a distinctive transcriptomic signature and a decreased differentiation program in isolated EEC from ObD compared to Ob individuals. In the second independent group of ObD, Ob and NOb individuals a decreased GLP-1 cell lineage and GLP-1 maturation from proglucagon, were observed in ObD compared to Ob individuals. Furthermore, jejunal density of GLP-1-positive cells was significantly reduced in ObD compared to Ob individuals. Conclusions These results highlight that the transcriptomic signature of EEC discriminate obese subjects according to their diabetic status. Furthermore, type 2 diabetes is associated with reduced GLP-1 cell differentiation and proglucagon maturation leading to low GLP-1-cell density in human obesity. These mechanisms could account for the decrease plasma GLP-1 observed in metabolic diseases.

Published
2020

3. Characterization and Pharmacological Validation of a Preclinical Model of NASH in Göttingen Minipigs

Author

Kevin Moreau, Valérie Paradis, Ludovic Lesage, Nicolas Lesueur, Franck Letourneur, Dominique Valla, Aurélie Helbert, Nathalie De Preville, Stéphanie Creusot, Adel Hammoutene, Tania Baltauss, Olivier Broux, Angelique Brzustowski, Philippe Delerive, Nicolas Provost, Edwige-Ludiwyne Hubert, Valérie Duvivier, Lindsay Gerard, Karine Lemaitre, Lucie Adoux, and Julia Geronimi

Subjects
medicine.medical_specialty, Cirrhosis, Hepatology, business.industry, nutritional and metabolic diseases, Obeticholic acid, Chronic liver disease, medicine.disease, digestive system, Gastroenterology, digestive system diseases, chemistry.chemical_compound, chemistry, Fibrosis, Internal medicine, Hepatocellular carcinoma, Nonalcoholic fatty liver disease, medicine, Steatosis, Metabolic syndrome, business
Abstract

Background Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, which is associated with features of metabolic syndrome. NAFLD may progress in a subset of patients into nonalcoholic steatohepatitis (NASH) with liver injury resulting ultimately in cirrhosis and potentially hepatocellular carcinoma. Today, there is no approved treatment for NASH due to, at least in part, the lack of preclinical models recapitulating features of human disease. Here, we report the development of a dietary model of NASH in the Gottingen minipig. Methods First, we performed a longitudinal characterization of diet-induced NASH and fibrosis using biochemical, histological, and transcriptional analyses. We then evaluated the pharmacological response to Obeticholic acid (OCA) treatment for 8 weeks at 2.5mg/kg/d, a dose matching its active clinical exposure. Results Serial histological examinations revealed a rapid installation of NASH driven by massive steatosis and inflammation, including evidence of ballooning. Furthermore, we found the progressive development of both perisinusoidal and portal fibrosis reaching fibrotic septa after 6 months of diet. Histological changes were mechanistically supported by well-defined gene signatures identified by RNA Seq analysis. While treatment with OCA was well tolerated throughout the study, it did not improve liver dysfunction nor NASH progression. By contrast, OCA treatment resulted in a significant reduction in diet-induced fibrosis in this model. Conclusions These results, taken together, indicate that the diet-induced NASH in the Gottingen minipig recapitulates most of the features of human NASH and may be a model with improved translational value to prioritize drug candidates toward clinical development

Published
2021

4. Mineralocorticoid Receptor Mutations Differentially Affect Individual Gene Expression Profiles in Pseudohypoaldosteronism Type 1

Author

Fábio L. Fernandes-Rosa, Sonir Roberto Rauber Antonini, Jérôme Fagart, Maria-Christina Zennaro, Arndt Benecke, Xavier Jeunemaitre, Marie-Edith Rafestin-Oblin, Nicolas Tchitchek, Edwige-Ludiwyne Hubert, Elodie Jouanno, and Débora Aline Silva Gomes

Subjects
Models, Molecular, Transcriptional Activation, Heterozygote, medicine.medical_specialty, Pseudohypoaldosteronism, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Gene Expression, Biology, medicine.disease_cause, Biochemistry, chemistry.chemical_compound, Endocrinology, Mineralocorticoid receptor, Internal medicine, medicine, Humans, Receptor, Aldosterone, Genetics, Mutation, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Biochemistry (medical), Heterozygote advantage, medicine.disease, Phenotype, Pedigree, Gene expression profiling, Receptors, Mineralocorticoid, chemistry, Protein Biosynthesis, RNA, hormones, hormone substitutes, and hormone antagonists, Plasmids
Abstract

Type 1 pseudohypoaldosteronism (PHA1), a primary form of mineralocorticoid resistance, is due to inactivating mutations of the NR3C2 gene, coding for the mineralocorticoid receptor (MR).The objective of the study was to assess whether different NR3C2 mutations have distinct effects on the pattern of MR-dependent transcriptional regulation of aldosterone-regulated genes.Four MR mutations affecting residues in the ligand binding domain, identified in families with PHA1, were tested. MR proteins generated by site-directed mutagenesis were analyzed for their binding to aldosterone and were transiently transfected into renal cells to explore the functional effects on the transcriptional activity of the receptors by cis-trans-cotransactivation assays and by measuring the induction of endogenous gene transcription.Binding assays showed very low or absent aldosterone binding for mutants MR(877Pro), MR(848Pro), and MR(947stop) and decreased affinity for aldosterone of MR(843Pro). Compared with wild-type MR, the mutations p.Leu843Pro and p.Leu877Pro displayed half-maximal aldosterone-dependent transactivation of reporter genes driven by mouse mammary tumor virus or glucocorticoid response element-2 dependent promoters, whereas MR(848Pro) and MR(947stop) nearly or completely lost transcriptional activity. Although MR(848Pro) and MR(947stop) were also incapable of inducing aldosterone-dependent gene expression of endogenous sgk1, GILZ, NDRG2, and SCNN1A, MR(843Pro) retained complete transcriptional activity on sgk1 and GILZ gene expression, and MR(877Pro) negatively affected the expression of sgk1, NDRG2, and SCNN1A.Our data demonstrate that MR mutations differentially affect individual gene expression in a promoter-dependent manner. Investigation of differential gene expression profiles in PHA1 may allow a better understanding of the molecular substrate of phenotypic variability and to elucidate pathogenic mechanisms underlying the disease.

Published
2011

5. Mineralocorticoid Receptor Mutations and a Severe Recessive Pseudohypoaldosteronism Type 1

Author

Raphaël Teissier, Edwige-Ludiwyne Hubert, Fabio L. Fernandes-Rosa, Michel Fay, Marie-Edith Rafestin-Oblin, Maria-Christina Zennaro, Xavier Jeunemaitre, Chantal Metz, and Brigitte Escoubet

Subjects
Male, medicine.medical_specialty, medicine.drug_class, Pseudohypoaldosteronism, Population, 030209 endocrinology & metabolism, Biology, Severity of Illness Index, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Mineralocorticoid receptor, Internal medicine, Chlorocebus aethiops, medicine, Animals, Humans, Allele, education, Aldosterone, Gene, 030304 developmental biology, Family Health, Genetics, 0303 health sciences, education.field_of_study, Infant, Newborn, General Medicine, medicine.disease, Failure to Thrive, Pedigree, Receptors, Mineralocorticoid, Basic Research, Endocrinology, chemistry, Codon, Nonsense, Nephrology, Mineralocorticoid, Child, Preschool, COS Cells, Failure to thrive, Codon, Terminator, Female, medicine.symptom, Hyponatremia, Protein Binding
Abstract

Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease of mineralocorticoid resistance characterized by salt wasting and failure to thrive in infancy. Here we describe the first case of a newborn with severe recessive PHA1 caused by two heterozygous mutations in NR3C2, gene coding for the mineralocorticoid receptor (MR). Independent segregation of the mutations occurred in the family, with p.Ser166X being transmitted from the affected father and p.Trp806X from the asymptomatic mother Whereas the truncated MR(166X) protein was degraded, MR(806X) was expressed both at the mRNA and protein level. Functional studies demonstrated that despite its inability to bind aldosterone, MR(806X) had partial ligand-independent transcriptional activity. Partial nuclear localization of MR(806X) in the absence of hormone was identified as a prerequisite to initiate transcription. This exceptional case broadens the spectrum of clinical phenotypes of PHA1 and demonstrates that minimal residual activity of MR is compatible with life. It also suggests that rare hypomorphic NR3C2 alleles may be more common than expected from the prevalence of detected PHA1 cases. This might prove relevant for patient's care in neonatal salt losing disorders and may affect renal salt handling and blood pressure in the general population.

Published
2011
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6. Jejunal T Cell Inflammation in Human Obesity Correlates with Decreased Enterocyte Insulin Signaling

Author

Aurelie Cotillard, Romain Remark, Karine Clément, Omran Allatif, Christine Poitou, Céline Osinski, Carla Mendes-Sá, Catherine Sautès-Fridman, Milena Monteiro-Sepulveda, Hélène Fohrer-Ting, Laurent Genser, Sébastien André, Sothea Touch, Armelle Leturque, Edwige-Ludiwyne Hubert, Kevin Garbin, Joan Tordjman, Edith Brot-Laroche, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Laboratoire de chimie Macromoléculaire (CNRS UMR 5076), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), 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), BioInformatique et BioStatistiques (BIBS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Innate Pharma, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Metabolisme et Differenciation Intestinale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), FOHRER-TING, Hélène, Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), École pratique des hautes études (EPHE), Service de nutrition [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Physiology, medicine.medical_treatment, T-Lymphocytes, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 0302 clinical medicine, Insulin, Intestinal Mucosa, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, Glucose Transporter Type 2, 0303 health sciences, biology, Middle Aged, medicine.anatomical_structure, Cytokine, Jejunum, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Female, medicine.symptom, Signal Transduction, Adult, medicine.medical_specialty, Enterocyte, CD8 Antigens, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Insulin resistance, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Obesity, Molecular Biology, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, 030304 developmental biology, Lamina propria, Lipid metabolism, Cell Biology, medicine.disease, Insulin receptor, Endocrinology, Enterocytes, Immunology, biology.protein, Insulin Resistance
Abstract

SummaryIn obesity, insulin resistance is linked to inflammation in several tissues. Although the gut is a very large lymphoid tissue, inflammation in the absorptive small intestine, the jejunum, where insulin regulates lipid and sugar absorption is unknown. We analyzed jejunal samples of 185 obese subjects stratified in three metabolic groups: without comorbidity, suffering from obesity-related comorbidity, and diabetic, versus 33 lean controls. Obesity increased both mucosa surface due to lower cell apoptosis and innate and adaptive immune cell populations. The preferential CD8αβ T cell location in epithelium over lamina propria appears a hallmark of obesity. Cytokine secretion by T cells from obese, but not lean, subjects blunted insulin signaling in enterocytes relevant to apical GLUT2 mislocation. Statistical links between T cell densities and BMI, NAFLD, or lipid metabolism suggest tissue crosstalk. Obesity triggers T-cell-mediated inflammation and enterocyte insulin resistance in the jejunum with potential broader systemic implications.

Published
2015

8. Aldosterone resistance: structural and functional considerations and new perspectives

Author

Fabio L. Fernandes-Rosa, Maria-Christina Zennaro, and Edwige-Ludiwyne Hubert

Subjects
Epithelial sodium channel, medicine.medical_specialty, Hyperkalemia, Pseudohypoaldosteronism, Drug Resistance, Disease, Biology, Biochemistry, Models, Biological, chemistry.chemical_compound, Structure-Activity Relationship, Endocrinology, Mineralocorticoid receptor, Internal medicine, medicine, Animals, Humans, Protein Interaction Domains and Motifs, Epithelial Sodium Channels, Molecular Biology, Aldosterone, Genetic Association Studies, Metabolic acidosis, Water-Electrolyte Balance, medicine.disease, Receptors, Mineralocorticoid, chemistry, Failure to thrive, Mutation, Mutant Proteins, medicine.symptom
Abstract

Aldosterone plays an essential role in the maintenance of fluid and electrolyte homeostasis in the distal nephron. Loss-of-function mutations in two key components of the aldosterone response, the mineralocorticoid receptor and the epithelial sodium channel ENaC, lead to type 1 pseudohypoaldosteronism (PHA1), a rare genetic disease of aldosterone resistance characterized by salt wasting, dehydration, failure to thrive, hyperkalemia and metabolic acidosis. This review describes the clinical, biological and genetic characteristics of the different forms of PHA1 and highlights recent advances in the understanding of the pathogenesis of the disease. We will also discuss genotype-phenotype correlations and new clinical and genetic entities that may prove relevant for patient's care in neonates with renal salt losing syndromes and/or failure to thrive.

Published
2011

9. Analysis of insulin sensitivity in adipose tissue of patients with primary aldosteronism

Author

Paolo Mulatero, Alessandra Calcagno, Celso E. Gomez-Sanchez, Nicoletta Sonino, Alessandro Peschechera, Catia Pilon, Francesco Fallo, Riccardo Urbanet, Roberto Vettor, Edwige-Ludiwyne Hubert, Mariacristina Toffanin, Maria-Christina Zennaro, Francesco Giorgino, and Gilberta Giacchetti

Subjects
Male, medicine.medical_specialty, hypertension, Hydrocortisone, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Clinical Biochemistry, Blotting, Western, Adipose tissue, Intra-Abdominal Fat, Biochemistry, chemistry.chemical_compound, Endocrinology, Mineralocorticoid receptor, Insulin resistance, Adrenocorticotropic Hormone, Internal medicine, Hyperaldosteronism, Renin, medicine, Humans, Insulin, primary aldosteronism, RNA, Messenger, Aldosterone, Analysis of Variance, biology, Adiponectin, business.industry, Reverse Transcriptase Polymerase Chain Reaction, Leptin, Biochemistry (medical), medicine.disease, Immunohistochemistry, Adrenal Cortex Neoplasms, Insulin receptor, Receptors, Mineralocorticoid, chemistry, Adrenocortical Adenoma, biology.protein, Female, Insulin Resistance, business
Abstract

The objective of the study was to assess the effect of high aldosterone levels on insulin sensitivity of adipose tissue in humans.Visceral adipose tissue (VAT) was obtained from patients with aldosterone-producing adenoma (APA; n=14) and, as controls, nonfunctioning adenoma (NFA; n=14) undergoing laparoscopic adrenalectomy. Homeostasis model assessment index was higher and potassium was lower in APA than NFA (P0.05). Immunohistochemistry, Western blotting, and real-time PCR were used to detect and quantify mineralocorticoid receptor (MR) expression. Transcript levels of peroxisome proliferative-activated receptor-gamma, insulin receptor, glucose transporter 4, insulin receptor substrate-1 and -2, leptin, adiponectin, IL-6, monocyte chemoattractant protein-1, glucocorticoid receptor (GR)-alpha, 11beta-hydroxysteroid dehydrogenase (HSD11B) type 1, and HSD11B2 were quantified. The effect of increasing aldosterone concentrations on 2-deoxy-[3H]d-glucose uptake was tested in human sc abdominal adipocytes.Expression of MR was demonstrated in VAT, with no difference between APA and NFA as to mRNA levels of MR, GRalpha, HSD11B1, and glucose metabolism and inflammation factors. In cultured adipocytes, basal and insulin-stimulated glucose uptake were unaffected by 1-100 nM (normal/hyperaldosteronism) and impaired only by much higher, up to 10 microM, aldosterone concentrations. The impairment was prevented by RU486 but not by eplerenone.Gene expression of insulin signaling/inflammatory molecules was similar in VAT of APA and NFA patients, not supporting an effect of aldosterone excess on insulin sensitivity of adipose tissues. Only at pharmacological concentrations and through GR activation, aldosterone reduced glucose uptake in adipocytes. Insulin resistance in primary aldosteronism might occur in compartments other than fat and/or depend on concurrent environmental factors.

Published
2010

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