Modeling Human Bile Acid Transport and Synthesis in Stem Cell-Derived Hepatocytes with a Patient-Specific Mutation.
ATP Binding Cassette Transporter, Subfamily B, Member 11
/ physiology
Bile Acids and Salts
/ metabolism
Biological Transport
CRISPR-Cas Systems
Cell Culture Techniques
/ methods
Cell Differentiation
Cells, Cultured
Gene Editing
Hepatocytes
/ cytology
Humans
Induced Pluripotent Stem Cells
/ cytology
Models, Biological
Mutation
CRISPR genome editing
PFIC2
bile acid synthesis
bile acid transport
hepatic differentiation
iPSC
progressive familial intrahepatic cholestasis
Journal
Stem cell reports
ISSN: 2213-6711
Titre abrégé: Stem Cell Reports
Pays: United States
ID NLM: 101611300
Informations de publication
Date de publication:
09 02 2021
09 02 2021
Historique:
received:
06
01
2020
revised:
13
12
2020
accepted:
14
12
2020
pubmed:
16
1
2021
medline:
30
11
2021
entrez:
15
1
2021
Statut:
ppublish
Résumé
The bile salt export pump (BSEP) is responsible for the export of bile acid from hepatocytes. Impaired transcellular transport of bile acids in hepatocytes with mutations in BSEP causes cholestasis. Compensatory mechanisms to regulate the intracellular bile acid concentration in human hepatocytes with BSEP deficiency remain unclear. To define pathways that prevent cytotoxic accumulation of bile acid in hepatocytes, we developed a human induced pluripotent stem cell-based model of isogenic BSEP-deficient hepatocytes in a Transwell culture system. Induced hepatocytes (i-Heps) exhibited defects in the apical export of bile acids but maintained a low intracellular bile acid concentration by inducing basolateral export. Modeling the autoregulation of bile acids on hepatocytes, we found that BSEP-deficient i-Heps suppressed de novo bile acid synthesis using the FXR pathway via basolateral uptake and export without apical export. These observations inform the development of therapeutic targets to reduce the overall bile acid pool in patients with BSEP deficiency.
Identifiants
pubmed: 33450190
pii: S2213-6711(20)30503-8
doi: 10.1016/j.stemcr.2020.12.008
pmc: PMC7878720
pii:
doi:
Substances chimiques
ATP Binding Cassette Transporter, Subfamily B, Member 11
0
Bile Acids and Salts
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
309-323Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK107553
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK120765
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK078392
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107530
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK123181
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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