In Vitro Rescue of the Bile Acid Transport Function of ABCB11 Variants by CFTR Potentiators
ABCB11 is responsible for biliary bile acid secretion at the canalicular membrane of hepatocytes. Variations in the <i>ABCB11</i> gene cause a spectrum of rare liver diseases. The most severe form is progressive familial intrahepatic cholestasis type 2 (PFIC2). Current medical treatments...
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MDPI AG
2022-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/18/10758 |
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| author | Elodie Mareux Martine Lapalus Amel Ben Saad Renaud Zelli Mounia Lakli Yosra Riahi Marion Almes Manon Banet Isabelle Callebaut Jean-Luc Decout Thomas Falguières Emmanuel Jacquemin Emmanuel Gonzales |
| author_facet | Elodie Mareux Martine Lapalus Amel Ben Saad Renaud Zelli Mounia Lakli Yosra Riahi Marion Almes Manon Banet Isabelle Callebaut Jean-Luc Decout Thomas Falguières Emmanuel Jacquemin Emmanuel Gonzales |
| author_sort | Elodie Mareux |
| collection | DOAJ |
| description | ABCB11 is responsible for biliary bile acid secretion at the canalicular membrane of hepatocytes. Variations in the <i>ABCB11</i> gene cause a spectrum of rare liver diseases. The most severe form is progressive familial intrahepatic cholestasis type 2 (PFIC2). Current medical treatments have limited efficacy. Here, we report the in vitro study of Abcb11 missense variants identified in PFIC2 patients and their functional rescue using cystic fibrosis transmembrane conductance regulator potentiators. Three ABCB11 disease-causing variations identified in PFIC2 patients (i.e., A257V, T463I and G562D) were reproduced in a plasmid encoding an Abcb11-green fluorescent protein. After transfection, the expression and localization of the variants were studied in HepG2 cells. Taurocholate transport activity and the effect of potentiators were studied in Madin–Darby canine kidney (MDCK) clones coexpressing Abcb11 and the sodium taurocholate cotransporting polypeptide (Ntcp/<i>Slc10A1</i>). As predicted using three-dimensional structure analysis, the three variants were expressed at the canalicular membrane but showed a defective function. Ivacaftor, GLP1837, SBC040 and SBC219 potentiators increased the bile acid transport of A257V and T463I and to a lesser extent, of G562D Abcb11 missense variants. In addition, a synergic effect was observed when ivacaftor was combined with SBC040 or SBC219. Such potentiators could represent new pharmacological approaches for improving the condition of patients with ABCB11 deficiency due to missense variations affecting the function of the transporter. |
| first_indexed | 2024-03-09T23:43:28Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:43:28Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0873ff64b92c4ee2bf9d64c9d6d384912023-11-23T16:47:32ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123181075810.3390/ijms231810758In Vitro Rescue of the Bile Acid Transport Function of ABCB11 Variants by CFTR PotentiatorsElodie Mareux0Martine Lapalus1Amel Ben Saad2Renaud Zelli3Mounia Lakli4Yosra Riahi5Marion Almes6Manon Banet7Isabelle Callebaut8Jean-Luc Decout9Thomas Falguières10Emmanuel Jacquemin11Emmanuel Gonzales12Inserm UMR_S 1193, Physiopathogénèse et Traitement des Maladies du Foie, Université Paris-Saclay, FHU Hepatinov, 91400 Orsay, FranceInserm UMR_S 1193, Physiopathogénèse et Traitement des Maladies du Foie, Université Paris-Saclay, FHU Hepatinov, 91400 Orsay, FranceInserm UMR_S 1193, Physiopathogénèse et Traitement des Maladies du Foie, Université Paris-Saclay, FHU Hepatinov, 91400 Orsay, FranceUniversité Grenoble Alpes, CNRS, UMR CNRS 5063, DPM, 38000 Grenoble, FranceInserm UMR_S 1193, Physiopathogénèse et Traitement des Maladies du Foie, Université Paris-Saclay, FHU Hepatinov, 91400 Orsay, FranceInserm UMR_S 1193, Physiopathogénèse et Traitement des Maladies du Foie, Université Paris-Saclay, FHU Hepatinov, 91400 Orsay, FranceAssistance Publique-Hôpitaux de Paris, Pediatric Hepatology & Pediatric Liver Transplant Department, Reference Center for Rare Pediatric Liver Diseases, FILFOIE, ERN Rare-Liver, Faculté de Médecine Paris-Saclay, CHU Bicêtre, 94270 Le Kremlin-Bicêtre, FranceInserm UMR_S 1193, Physiopathogénèse et Traitement des Maladies du Foie, Université Paris-Saclay, FHU Hepatinov, 91400 Orsay, FranceMuséum National d’Histoire Naturelle, UMR CNRS 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie (IMPMC), Sorbonne Université, 75005 Paris, FranceUniversité Grenoble Alpes, CNRS, UMR CNRS 5063, DPM, 38000 Grenoble, FranceInserm UMR_S 1193, Physiopathogénèse et Traitement des Maladies du Foie, Université Paris-Saclay, FHU Hepatinov, 91400 Orsay, FranceInserm UMR_S 1193, Physiopathogénèse et Traitement des Maladies du Foie, Université Paris-Saclay, FHU Hepatinov, 91400 Orsay, FranceInserm UMR_S 1193, Physiopathogénèse et Traitement des Maladies du Foie, Université Paris-Saclay, FHU Hepatinov, 91400 Orsay, FranceABCB11 is responsible for biliary bile acid secretion at the canalicular membrane of hepatocytes. Variations in the <i>ABCB11</i> gene cause a spectrum of rare liver diseases. The most severe form is progressive familial intrahepatic cholestasis type 2 (PFIC2). Current medical treatments have limited efficacy. Here, we report the in vitro study of Abcb11 missense variants identified in PFIC2 patients and their functional rescue using cystic fibrosis transmembrane conductance regulator potentiators. Three ABCB11 disease-causing variations identified in PFIC2 patients (i.e., A257V, T463I and G562D) were reproduced in a plasmid encoding an Abcb11-green fluorescent protein. After transfection, the expression and localization of the variants were studied in HepG2 cells. Taurocholate transport activity and the effect of potentiators were studied in Madin–Darby canine kidney (MDCK) clones coexpressing Abcb11 and the sodium taurocholate cotransporting polypeptide (Ntcp/<i>Slc10A1</i>). As predicted using three-dimensional structure analysis, the three variants were expressed at the canalicular membrane but showed a defective function. Ivacaftor, GLP1837, SBC040 and SBC219 potentiators increased the bile acid transport of A257V and T463I and to a lesser extent, of G562D Abcb11 missense variants. In addition, a synergic effect was observed when ivacaftor was combined with SBC040 or SBC219. Such potentiators could represent new pharmacological approaches for improving the condition of patients with ABCB11 deficiency due to missense variations affecting the function of the transporter.https://www.mdpi.com/1422-0067/23/18/10758BSEPcholestasisVX-770potentiatorABC transporterpediatrics |
| spellingShingle | Elodie Mareux Martine Lapalus Amel Ben Saad Renaud Zelli Mounia Lakli Yosra Riahi Marion Almes Manon Banet Isabelle Callebaut Jean-Luc Decout Thomas Falguières Emmanuel Jacquemin Emmanuel Gonzales In Vitro Rescue of the Bile Acid Transport Function of ABCB11 Variants by CFTR Potentiators International Journal of Molecular Sciences BSEP cholestasis VX-770 potentiator ABC transporter pediatrics |
| title | In Vitro Rescue of the Bile Acid Transport Function of ABCB11 Variants by CFTR Potentiators |
| title_full | In Vitro Rescue of the Bile Acid Transport Function of ABCB11 Variants by CFTR Potentiators |
| title_fullStr | In Vitro Rescue of the Bile Acid Transport Function of ABCB11 Variants by CFTR Potentiators |
| title_full_unstemmed | In Vitro Rescue of the Bile Acid Transport Function of ABCB11 Variants by CFTR Potentiators |
| title_short | In Vitro Rescue of the Bile Acid Transport Function of ABCB11 Variants by CFTR Potentiators |
| title_sort | in vitro rescue of the bile acid transport function of abcb11 variants by cftr potentiators |
| topic | BSEP cholestasis VX-770 potentiator ABC transporter pediatrics |
| url | https://www.mdpi.com/1422-0067/23/18/10758 |
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