{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T03:52:02Z","timestamp":1791863522782,"version":"4.3.4"},"reference-count":56,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T00:00:00Z","timestamp":1748476800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Minist\u00e8re de l\u2019Enseignement Sup\u00e9rieur, de la Recherche et de l\u2019Innovation","award":["ANR-21-CE18-0030-01"],"award-info":[{"award-number":["ANR-21-CE18-0030-01"]}]},{"name":"Association pour la Recherche en H\u00e9patologie P\u00e9diatrique","award":["ANR-21-CE18-0030-01"],"award-info":[{"award-number":["ANR-21-CE18-0030-01"]}]},{"name":"Association Maladies du Foie depuis l\u2019Enfance","award":["ANR-21-CE18-0030-01"],"award-info":[{"award-number":["ANR-21-CE18-0030-01"]}]},{"name":"IPSEN Pharma (Boulogne-Billancourt, France)","award":["ANR-21-CE18-0030-01"],"award-info":[{"award-number":["ANR-21-CE18-0030-01"]}]},{"name":"Fili\u00e8re de sant\u00e9 des maladies rares du foie (FILFOIE, Paris, France)","award":["ANR-21-CE18-0030-01"],"award-info":[{"award-number":["ANR-21-CE18-0030-01"]}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-21-CE18-0030-01"],"award-info":[{"award-number":["ANR-21-CE18-0030-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a severe hepatocellular cholestasis due to biallelic variations in the ABCB11 (ATP-binding cassette B11) gene encoding the canalicular bile salt export pump (BSEP). Some missense variants identified in patients with PFIC2 do not traffic properly to the canalicular membrane. However, 4-phenybutyrate (4-PB) has been shown in vitro to partially correct the mis-trafficking of selected variants, resulting in an improvement of the medical conditions of corresponding PFIC2 patients. Herein, we report the ability of 4-PB analogous or homologous drugs and of non-4-PB related chemical correctors to rescue the canalicular expression and the activity of the folding-defective Abcb11R1128C variant. New compounds, either identified by screening a chemical library or designed by structural homology with 4-PB (or its metabolites) and synthesized, were evaluated in vitro for their ability to (i) correct the canalicular localization of Abcb11R1128C after transfection in hepatocellular polarized cell lines; (ii) restore the 3H-taurocholate transport of the Abcb11R1128C protein in Madin\u2013Darby canine kidney (MDCK) cells stably co-expressing Abcb11 and the sodium taurocholate co-transporting polypeptide (Ntcp\/Slc10A1). Glycerol phenylbutyrate (GPB), phenylacetate (PA, the active metabolite of 4-PB), 3-hydroxy-2-methyl-4-phenylbutyrate (HMPB, a 4-PB metabolite analog chemically synthesized in our laboratory) and 4-oxo-1,2,3,4-tetrahydro-naphthalene-carboxylate (OTNC, from the chemical library screening) significantly increased the proportion of canalicular Abcb11R1128C protein. GPB, PA, ursodeoxycholic acid (UDCA), alone or in combination with 4-PB, suberoylanilide hydroxamic acid (SAHA), C18, VX-445, and\/or VX-661, significantly corrected both the traffic and the activity of Abcb11R1128C. Such correctors could represent new pharmacological insights for improving the condition of patients with ABCB11 deficiency due to missense variations affecting the transporter\u2019s traffic.<\/jats:p>","DOI":"10.3390\/ijms26115232","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T09:47:34Z","timestamp":1748512054000},"page":"5232","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Correction of a Traffic-Defective Missense ABCB11 Variant Responsible for Progressive Familial Intrahepatic Cholestasis Type 2"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7033-831X","authenticated-orcid":false,"given":"Martine","family":"Lapalus","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiopathog\u00e9n\u00e8se et Traitement des Maladies du Foie, FHU Hepatinov, 91400 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0474-9217","authenticated-orcid":false,"given":"Elodie","family":"Mareux","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiopathog\u00e9n\u00e8se et Traitement des Maladies du Foie, FHU Hepatinov, 91400 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachida","family":"Amzal","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiopathog\u00e9n\u00e8se et Traitement des Maladies du Foie, FHU Hepatinov, 91400 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1995-2696","authenticated-orcid":false,"given":"Emmanuelle","family":"Dr\u00e8ge","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, CNRS, BioCIS, 91400 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8210-166X","authenticated-orcid":false,"given":"Yosra","family":"Riahi","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiopathog\u00e9n\u00e8se et Traitement des Maladies du Foie, FHU Hepatinov, 91400 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvain","family":"Petit","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, CNRS, BioCIS, 91400 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3042-4776","authenticated-orcid":false,"given":"Manon","family":"Banet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiopathog\u00e9n\u00e8se et Traitement des Maladies du Foie, FHU Hepatinov, 91400 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2867-0500","authenticated-orcid":false,"given":"Thomas","family":"Falgui\u00e8res","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiopathog\u00e9n\u00e8se et Traitement des Maladies du Foie, FHU Hepatinov, 91400 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3124-887X","authenticated-orcid":false,"given":"Isabelle","family":"Callebaut","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Mus\u00e9um National d\u2019Histoire Naturelle, CNRS, Institut de Min\u00e9ralogie, de Physique des Mat\u00e9riaux et de Cosmochimie (IMPMC), 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4226-8489","authenticated-orcid":false,"given":"Bruno","family":"Figad\u00e8re","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, CNRS, BioCIS, 91400 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Joseph","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, CNRS, BioCIS, 91400 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1546-3193","authenticated-orcid":false,"given":"Emmanuel","family":"Gonzales","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiopathog\u00e9n\u00e8se et Traitement des Maladies du Foie, FHU Hepatinov, 91400 Orsay, France"},{"name":"Assistance Publique-H\u00f4pitaux de Paris, Pediatric Hepatology and Pediatric Liver Transplant Department, Reference Center for Rare Pediatric Liver Diseases, FILFOIE, ERN Rare-Liver, Facult\u00e9 de M\u00e9decine Paris-Saclay, CHU Bic\u00eatre, 94270 Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7536-6272","authenticated-orcid":false,"given":"Emmanuel","family":"Jacquemin","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Inserm, Physiopathog\u00e9n\u00e8se et Traitement des Maladies du Foie, FHU Hepatinov, 91400 Orsay, France"},{"name":"Assistance Publique-H\u00f4pitaux de Paris, Pediatric Hepatology and Pediatric Liver Transplant Department, Reference Center for Rare Pediatric Liver Diseases, FILFOIE, ERN Rare-Liver, Facult\u00e9 de M\u00e9decine Paris-Saclay, CHU Bic\u00eatre, 94270 Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1002\/hep.23539","article-title":"ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): Phenotypic differences between PFIC1 and PFIC2 and natural history","volume":"51","author":"Fabre","year":"2010","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1053\/j.gastro.2008.01.038","article-title":"Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families","volume":"134","author":"Strautnieks","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1002\/hep.31476","article-title":"Pharmacological Premature Termination Codon Readthrough of ABCB11 in 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