{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:09:15Z","timestamp":1792001355059,"version":"4.4.0"},"reference-count":34,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2020,6,8]],"date-time":"2020-06-08T00:00:00Z","timestamp":1591574400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background &amp; Aim<\/jats:title><jats:p>The canalicular bile salt export pump (BSEP\/<jats:italic>ABCB11<\/jats:italic>) of hepatocytes is the main adenosine triphosphate (ATP)\u2010binding cassette (ABC) transporter responsible for bile acid secretion. Mutations in <jats:italic>ABCB11<\/jats:italic> 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\/<jats:italic>ABCC7<\/jats:italic>) potentiator.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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\u2010green fluorescent protein. After transfection, mutant expression was studied in Can 10 cells. Taurocholate transport activity and ivacaftor effect were studied in Madin\u2010Darby canine kidney (MDCK) clones co\u2010expressing the rat sodium\u2010taurocholate co\u2010transporting polypeptide (Ntcp\/<jats:italic>Slc10A1<\/jats:italic>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>As the wild\u2010type protein, Bsep<jats:sup>T463I<\/jats:sup> 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 Bsep<jats:sup>T463I<\/jats:sup>. Ivacaftor treatment increased by 1.7\u2010fold taurocholate transport activity of Bsep<jats:sup>T463I<\/jats:sup> (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.0001), reaching 95% of Bsep<jats:sup>wt<\/jats:sup> activity. These data suggest that the p.T463I mutation impairs ATP\u2010binding, resulting in Bsep dysfunction that can be rescued by ivacaftor.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results provide experimental evidence of ivacaftor therapeutic potential for selected patients with PFIC2 caused by <jats:italic>ABCB11<\/jats:italic> missense mutations affecting BSEP function. This could represent a significant step forward for the care of patients with BSEP deficiency.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.14518","type":"journal-article","created":{"date-parts":[[2020,5,20]],"date-time":"2020-05-20T20:13:20Z","timestamp":1590005600000},"page":"1917-1925","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Functional rescue of an ABCB11 mutant by ivacaftor: A new targeted pharmacotherapy approach in bile salt export pump deficiency"],"prefix":"10.1111","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0474-9217","authenticated-orcid":false,"given":"Elodie","family":"Mareux","sequence":"first","affiliation":[{"name":"Inserm Physiopathog\u00e9n\u00e8se et traitement des maladies du foie UMR_S 1193 Hepatinov Universit\u00e9 Paris\u2010Saclay Orsay 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