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Article Dans Une Revue International Journal of Molecular Sciences Année : 2022

In Vitro Rescue of the Bile Acid Transport Function of ABCB11 Variants by CFTR Potentiators

Résumé

ABCB11 is responsible for biliary bile acid secretion at the canalicular membrane of hepatocytes. Variations in the ABCB11 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 Citation: Mareux, E.; Lapalus, M.; Ben Saad, A.; Zelli, R.; Lakli, M.; Riahi, Y.; Almes, M.; Banet, M.; Callebaut, I.; Decout, J.-L.; et al. In Vitro Rescue of the Bile Acid Transport Function of ABCB11 Variants by CFTR Potentiators. Int. J. Mol. Sci. 2022, 23, 10758. https:// doi.org/10.3390/ijms231810758 Academic Editor: Cesare Indiveri Received: 11 August 2022 Accepted: 13 September 2022 Published: 15 September 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 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/Slc10A1). 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.
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hal-03835703 , version 1 (01-11-2022)

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Elodie Mareux, Martine Lapalus, Amel Ben Saad, Renaud Zelli, Mounia Lakli, et al.. In Vitro Rescue of the Bile Acid Transport Function of ABCB11 Variants by CFTR Potentiators. International Journal of Molecular Sciences, 2022, 23 (18), pp.10758. ⟨10.3390/ijms231810758⟩. ⟨hal-03835703⟩
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