Modeling Human Bile Acid Transport and Synthesis in Stem Cell-Derived Hepatocytes with a Patient-Specific Mutation.
Stem Cell Reports
; 16(2): 309-323, 2021 02 09.
Article
en En
| MEDLINE
| ID: mdl-33450190
ABSTRACT
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.
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Banco de datos:
MEDLINE
Asunto principal:
Ácidos y Sales Biliares
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Hepatocitos
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Células Madre Pluripotentes Inducidas
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Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP
Límite:
Humans
Idioma:
En
Año:
2021
Tipo del documento:
Article