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Functional rescue of an ABCB11 mutant by ivacaftor: A new targeted pharmacotherapy approach in bile salt export pump deficiency
- Source :
- Liver International, Liver International, 2020, 40 (8), pp.1917-1925. ⟨10.1111/liv.14518⟩
- Publication Year :
- 2019
-
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
- 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
Subjects
Details
- ISSN :
- 14783231 and 14783223
- Volume :
- 40
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Liver international : official journal of the International Association for the Study of the LiverREFERENCES
- Accession number :
- edsair.doi.dedup.....79614830d82869c11c3cb1db00f0af71