Modeling Human Bile Acid Transport and Synthesis in Stem Cell-Derived Hepatocytes with a Patient-Specific Mutation

Hisamitsu Hayashi, Shuhei Osaka, Kokoro Sakabe, Aiko Fukami, Eriko Kishimoto, Eitaro Aihara, Yusuke Sabu, Ayumu Mizutani, Hiroyuki Kusuhara, Nakayuki Naritaka, Wujuan Zhang, Stacey S. Huppert, Masahide Sakabe, Takahisa Nakamura, Yueh Chiang Hu, Christopher Mayhew, Kenneth Setchell, Takanori Takebe, Akihiro Asai

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)309-323
Number of pages15
JournalStem Cell Reports
Volume16
Issue number2
DOIs
Publication statusPublished - 2021 Feb 9
Externally publishedYes

Keywords

  • CRISPR genome editing
  • PFIC2
  • bile acid synthesis
  • bile acid transport
  • hepatic differentiation
  • iPSC
  • progressive familial intrahepatic cholestasis

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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