@article{8b34bce2a66540a692b921b8c2b95c79,
title = "Modeling Human Bile Acid Transport and Synthesis in Stem Cell-Derived Hepatocytes with a Patient-Specific Mutation",
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.",
keywords = "bile acid synthesis, bile acid transport, CRISPR genome editing, hepatic differentiation, iPSC, PFIC2, progressive familial intrahepatic cholestasis",
author = "Hisamitsu Hayashi and Shuhei Osaka and Kokoro Sakabe and Aiko Fukami and Eriko Kishimoto and Eitaro Aihara and Yusuke Sabu and Ayumu Mizutani and Hiroyuki Kusuhara and Nakayuki Naritaka and Wujuan Zhang and Huppert, {Stacey S.} and Masahide Sakabe and Takahisa Nakamura and Hu, {Yueh Chiang} and Christopher Mayhew and Kenneth Setchell and Takanori Takebe and Akihiro Asai",
note = "Funding Information: We thank Drs. William Balistreri, Jorge A. Bezerra, and James Wells for their advice in scientific discussion and manuscript preparation. We thank Sanjay Subramanian for his work in immunohistochemistry experiments. We also thank Drs. K. Eto, M. Otsu, and H. Nakauchi at Tokyo University and Dr. Yamanaka at CiRA for providing iPSCs. This work was supported by NIH grant P30 DK078392, a Pilot & Feasibility Award, the AASLD Foundation (Pinnacle Research Award), the NASPGHAN Foundation (George Ferry Young Investigator Award), the Cincinnati Children's Research Foundation (Procter Scholar Award) to A.A. and NIH R01DK107530 and NIH R01DK123181 to T.N. Funding Information: We thank Drs. William Balistreri, Jorge A. Bezerra, and James Wells for their advice in scientific discussion and manuscript preparation. We thank Sanjay Subramanian for his work in immunohistochemistry experiments. We also thank Drs. K. Eto, M. Otsu, and H. Nakauchi at Tokyo University and Dr. Yamanaka at CiRA for providing iPSCs. This work was supported by NIH grant P30 DK078392 , a Pilot & Feasibility Award, the AASLD Foundation (Pinnacle Research Award), the NASPGHAN Foundation (George Ferry Young Investigator Award), the Cincinnati Children's Research Foundation (Procter Scholar Award) to A.A., and NIH R01DK107530 and NIH R01DK123181 to T.N. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2021",
month = feb,
day = "9",
doi = "10.1016/j.stemcr.2020.12.008",
language = "English",
volume = "16",
pages = "309--323",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "2",
}