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2. In vitro functional rescue by ivacaftor of an ABCB11 variant involved in PFIC2 and intrahepatic cholestasis of pregnancy

Author

Isabelle Callebaut, Martine Lapalus, Emmanuel Jacquemin, Emmanuel Gonzales, Elodie Mareux, Amel Ben-Saad, Thomas Falguières, Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), and HAL-SU, Gestionnaire

Subjects
medicine.medical_specialty, Cholestasis, Intrahepatic, Quinolones, VX-770, Aminophenols, Gastroenterology, Ivacaftor, 03 medical and health sciences, 0302 clinical medicine, Cholestasis, ABC transporters superfamily, Internal medicine, medicine, Missense mutation, Humans, Pharmacology (medical), ABCB11, Letter to the Editor, Genetics (clinical), ATP Binding Cassette Transporter, Subfamily B, Member 11, 030304 developmental biology, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Progressive familial intrahepatic cholestasis, Paediatrics, General Medicine, Potentiator, medicine.disease, Ursodeoxycholic acid, 3. Good health, Pregnancy Complications, BSEP, Mutation, Medicine, 030211 gastroenterology & hepatology, ATP-Binding Cassette Transporters, Female, business, Cholestasis of pregnancy, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

Background ABCB11 variations are responsible for a spectrum of rare liver diseases, including progressive familial intrahepatic cholestasis type 2 (PFIC2) and intrahepatic cholestasis of pregnancy (ICP). Current medical treatment of these conditions mostly relies on ursodeoxycholic acid with limited efficacy. We report on the in vitro study of the p.A257V missense variant of ABCB11 identified in a PFIC2 patient and in her mother who experienced ICP. Results The Ala257 residue is located outside the ATP-binding site of ABCB11. We show that the p.A257V variant of ABCB11 is correctly expressed at the canalicular membrane of HepG2 cells but that its function significantly decreased when studied in MDCK cells. This functional defect can be fully rescued by Ivacaftor. Conclusion Ivacaftor could be considered as a new pharmacological tool able to respond to an unmet medical need for patients with ICP and PFIC2 due to ABCB11 variations affecting ABCB11 function, even when the residue involved is not located in an ATP-binding site of ABCB11.

Published
2021
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3. Effect of CFTR correctors on the traffic and the function of intracellularly retained ABCB4 variants

Author

Ágota Tóth, Emmanuel Jacquemin, Isabelle Garcin, Jean-Louis Delaunay, Chantal Housset, Florent Di Meo, Angelika Janaszkiewicz, Alix Bruneau, Thomas Falguières, Martine Lapalus, Anne-Marie Durand-Schneider, Tounsia Aït-Slimane, Elodie Mareux, Emmanuel Gonzales, Virginie Vauthier, Amel Ben Saad, Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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)-CHU Pitié-Salpêtrière [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Gestionnaire, Hal Sorbonne Université

Subjects
ATP Binding Cassette Transporter, Subfamily B, In silico, cholestatic liver diseases, [SDV]Life Sciences [q-bio], Cystic Fibrosis Transmembrane Conductance Regulator, ATP-binding cassette transporter, Cholestasis, Intrahepatic, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Secretion, Cholestasis, Hepatology, biology, Chemistry, Progressive familial intrahepatic cholestasis, Wild type, molecular docking, ABCB4, medicine.disease, Cystic fibrosis transmembrane conductance regulator, cell models, Cell biology, [SDV] Life Sciences [q-bio], Molecular Docking Simulation, Transmembrane domain, ABC transporters, 030220 oncology & carcinogenesis, biology.protein, Phosphatidylcholines, 030211 gastroenterology & hepatology, bile secretion, targeted pharmacotherapy
Abstract

International audience; Background & aim: ABCB4 is expressed at the canalicular membrane of hepatocytes. This ATP-binding cassette (ABC) transporter is responsible for the secretion of phosphatidylcholine into bile canaliculi. Missense genetic variations of ABCB4 are correlated with several rare cholestatic liver diseases, the most severe being progressive familial intrahepatic cholestasis type 3 (PFIC3). In a repurposing strategy to correct intracellularly retained ABCB4 variants, we tested 16 compounds previously validated as cystic fibrosis transmembrane conductance regulator (CFTR) correctors.Methods: The maturation, intracellular localization and activity of intracellularly retained ABCB4 variants were analyzed in cell models after treatment with CFTR correctors. In addition, in silico molecular docking calculations were performed to test the potential interaction of CFTR correctors with ABCB4.Results: We observed that the correctors C10, C13, and C17, as well as the combinations of C3 + C18 and C4 + C18, allowed the rescue of maturation and canalicular localization of four distinct traffic-defective ABCB4 variants. However, such treatments did not permit a rescue of the phosphatidylcholine secretion activity of these defective variants and were also inhibitory of the activity of wild type ABCB4. In silico molecular docking analyses suggest that these CFTR correctors might directly interact with transmembrane domains and/or ATP-binding sites of the transporter.Conclusion: Our results illustrate the uncoupling between the traffic and the activity of ABCB4 because the same molecules can rescue the traffic of defective variants while they inhibit the secretion activity of the transporter. We expect that this study will help to design new pharmacological tools with potential clinical interest.

Published
2021
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5. Molecular Regulation of Canalicular ABC Transporters

Author

Amel, Ben Saad, Alix, Bruneau, Elodie, Mareux, Martine, Lapalus, Jean-Louis, Delaunay, Emmanuel, Gonzales, Emmanuel, Jacquemin, Tounsia, Aït-Slimane, Thomas, Falguières, Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Gestionnaire, Hal Sorbonne Université

Subjects
Glycosylation, [SDV]Life Sciences [q-bio], Bile Canaliculi, Ubiquitination, ABCB1, ABCC2, Review, ABCB11, ABCB4, digestive system, Endocytosis, Multidrug Resistance-Associated Protein 2, lcsh:Chemistry, [SDV] Life Sciences [q-bio], lcsh:Biology (General), lcsh:QD1-999, Hepatocytes, ABCG5/G8, Animals, Humans, ATP-Binding Cassette Transporters, lcsh:QH301-705.5, bile secretion, molecular partners
Abstract

International audience; The ATP-binding cassette (ABC) transporters expressed at the canalicular membrane of hepatocytes mediate the secretion of several compounds into the bile canaliculi and therefore play a key role in bile secretion. Among these transporters, ABCB11 secretes bile acids, ABCB4 translocates phosphatidylcholine and ABCG5/G8 is responsible for cholesterol secretion, while ABCB1 and ABCC2 transport a variety of drugs and other compounds. The dysfunction of these transporters leads to severe, rare, evolutionary biliary diseases. The development of new therapies for patients with these diseases requires a deep understanding of the biology of these transporters. In this review, we report the current knowledge regarding the regulation of canalicular ABC transporters' folding, trafficking, membrane stability and function, and we highlight the role of molecular partners in these regulating mechanisms.

Published
2021
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6. Glycerol Phenylbutyrate Therapy in Progressive Familial Intrahepatic Cholestasis Type 2

Author

Marion Almes, Agathe Jobert, Emmanuel Gonzales, Elodie Mareux, Martine Lapalus, and Emmanuel Jacquemin

Subjects
Glycerol, medicine.medical_specialty, business.industry, Gastroenterology, Progressive familial intrahepatic cholestasis, Cholestasis, Intrahepatic, medicine.disease, Phenylbutyrates, chemistry.chemical_compound, chemistry, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, Humans, Glycerol phenylbutyrate, business
Published
2020

7. Pharmacological premature termination codon readthrough of ABCB11 in bile salt export pump deficiency: an in vitro study

Author

Anne Davit-Spraul, Elodie Mareux, Martine Lapalus, Emmanuel Gonzales, Alice Thébaut, M. Almes, Emmanuel Jacquemin, Olivier Namy, Brigitte Grosse, Rachida Amzal, Laure Bidou, Mauricette Collado-Hilly, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Génomique, Structure et Traduction (GST), Département Biologie des Génomes (DBG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, PTC124, [SDV]Life Sciences [q-bio], Nonsense mutation, Progressive familial intrahepatic cholestasis, Cholestasis, Intrahepatic, gentamicin, Transfection, Madin Darby Canine Kidney Cells, Cohort Studies, Mice, 03 medical and health sciences, Dogs, 0302 clinical medicine, Cholestasis, Correspondence, medicine, Animals, Humans, ABCB11, ATP Binding Cassette Transporter, Subfamily B, Member 11, Oxadiazoles, Kidney, Hepatology, Chemistry, Ursodeoxycholic Acid, HEK 293 cells, fungi, Hep G2 Cells, medicine.disease, Phenylbutyrates, Molecular biology, Bile Salt Export Pump, Ursodeoxycholic acid, 3. Good health, HEK293 Cells, 030104 developmental biology, medicine.anatomical_structure, Codon, Nonsense, BSEP, NIH 3T3 Cells, geneticin, 030211 gastroenterology & hepatology, Gentamicins, Signal Transduction, medicine.drug
Abstract

BACKGROUND AND AIMS Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a severe hepatocellular cholestasis due to biallelic mutations in ABCB11 encoding the canalicular bile salt export pump (BSEP). Nonsense mutations are responsible for the most severe phenotypes. The aim was to assess the ability of drugs to induce readthrough of six nonsense mutations (p.Y354X, p.R415X, p.R470X, p.R1057X, p.R1090X, and p.E1302X) identified in patients with PFIC2. APPROACH AND RESULTS The ability of G418, gentamicin, and PTC124 to induce readthrough was studied using a dual gene reporter system in NIH3T3 cells. The ability of gentamicin to induce readthrough and to lead to the expression of a full-length protein was studied in human embryonic kidney 293 (HEK293), HepG2, and Can 10 cells using immunodetection assays. The function of the gentamicin-induced full-length protein was studied by measuring the [3 H]-taurocholate transcellular transport in stable Madin-Darby canine kidney clones co-expressing Na+-taurocholate co-transporting polypeptide (Ntcp). Combinations of gentamicin and chaperone drugs (ursodeoxycholic acid, 4-phenylbutyrate [4-PB]) were investigated. In NIH3T3, aminoglycosides significantly increased the readthrough level of all mutations studied, while PTC124 only slightly increased the readthrough of p.E1302X. Gentamicin induced a readthrough of p.R415X, p.R470X, p.R1057X, and p.R1090X in HEK293 cells. The resulting full-length proteins localized within the cytoplasm, except for BsepR1090X , which was also detected at the plasma membrane of human embryonic kidney HEK293 and at the canalicular membrane of Can 10 and HepG2 cells. Additional treatment with 4-PB and ursodeoxycholic acid significantly increased the canalicular proportion of full-length BsepR1090X protein in Can 10 cells. In Madin-Darby canine kidney clones, gentamicin induced a 40% increase of the BsepR1090X [3 H]-taurocholate transport, which was further increased with additional 4-PB treatment. CONCLUSION This study constitutes a proof of concept for readthrough therapy in selected patients with PFIC2 with nonsense mutations.

Published
2020
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8. Functional rescue of an ABCB11 mutant by ivacaftor: A new targeted pharmacotherapy approach in bile salt export pump deficiency

Author

Marion Almes, Tounsia Aït-Slimane, Emmanuel Gonzales, Elodie Mareux, Emmanuel Jacquemin, Thomas Falguières, Rachida Amzal, Pauline Adnot, Mauricette Collado-Hilly, Martine Lapalus, Jean-Louis Delaunay, Anne Davit-Spraul, Isabelle Callebaut, Physiopathogénèse et Traitement des Maladies du Foie, Hôpital Paul Brousse-Université Paris-Saclay, Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), and Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
EG and EJ conceived and designed the study. EM, [SDV]Life Sciences [q-bio], ATP-binding cassette transporter, Cholestasis, Intrahepatic, Pharmacology, Quinolones, Aminophenols, Ivacaftor, Bile Acids and Salts, 03 medical and health sciences, 0302 clinical medicine, Dogs, medicine, Missense mutation, Animals, Humans, ABCB11, ATP Binding Cassette Transporter, Subfamily B, Member 11, SLC10A1, Hepatology, biology, Chemistry, Progressive familial intrahepatic cholestasis, EM ML EG and EJ conceived and designed the study. EM ML RA PA, medicine.disease, Bile Salt Export Pump, ML, Cystic fibrosis transmembrane conductance regulator, Rats, EM, 030220 oncology & carcinogenesis, biology.protein, 030211 gastroenterology & hepatology, RA, medicine.drug, PA
Abstract

BACKGROUND & AIM The canalicular bile salt export pump (BSEP/ABCB11) of hepatocytes is the main adenosine triphosphate (ATP)-binding cassette (ABC) transporter responsible for bile acid secretion. Mutations in ABCB11 cause several cholestatic diseases, including progressive familial intrahepatic cholestasis type 2 (PFIC2) often lethal in absence of liver transplantation. We investigated in vitro the effect and potential rescue of a BSEP mutation by ivacaftor, a clinically approved cystic fibrosis transmembrane conductance regulator (CFTR/ABCC7) potentiator. METHODS The p.T463I mutation, identified in a PFIC2 patient and located in a highly conserved ABC transporter motif, was studied by 3D structure modelling. The mutation was reproduced in a plasmid encoding a rat Bsep-green fluorescent protein. After transfection, mutant expression was studied in Can 10 cells. Taurocholate transport activity and ivacaftor effect were studied in Madin-Darby canine kidney (MDCK) clones co-expressing the rat sodium-taurocholate co-transporting polypeptide (Ntcp/Slc10A1). RESULTS As the wild-type protein, BsepT463I was normally targeted to the canalicular membrane of Can 10 cells. As predicted by 3D structure modelling, taurocholate transport activity was dramatically low in MDCK clones expressing BsepT463I . Ivacaftor treatment increased by 1.7-fold taurocholate transport activity of BsepT463I (P

Published
2019
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