Effect of microbial short-chain fatty acids on CYP3A4-mediated metabolic activation of human pluripotent stem cell-derived liver organoids

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Title
Effect of microbial short-chain fatty acids on CYP3A4-mediated metabolic activation of human pluripotent stem cell-derived liver organoids
Author(s)
Seon Ju Mun; Jaeseo Lee; Kyung-Sook ChungMi-Young SonMyung Jin Son
Bibliographic Citation
Cells, vol. 10, pp. 126-126
Publication Year
2021
Abstract
The early and accurate prediction of the hepatotoxicity of new drug targets during nonclinical drug development is important to avoid postmarketing drug withdrawals and late-stage failures. We previously established long-term expandable and functional human-induced pluripotent stem cell (iPSC)-derived liver organoids as an alternative source for primary human hepatocytes. However, PSC-derived organoids are known to present immature fetal characteristics. Here, we treated these liver organoids with microbial short-chain fatty acids (SCFAs) to improve metabolic maturation based on microenvironmental changes in the liver during postnatal development. The effects of the three main SCFA components (acetate, propionate, and butyrate) and their mixture on liver organoids were determined. Propionate (1 μM) significantly promoted the CYP3A4/CYP3A7 expression ratio, and acetate (1 μM), propionate (1 μM), and butyrate (1 μM) combination treatment, compared to no treatment (control), substantially increased CYP3A4 activity and albumin secretion, as well as gene expression. More importantly, mixed SCFA treatment accurately revealed troglitazone-induced hepatotoxicity, which was redeemed on a potent CYP3A4 inhibitor ketoconazole treatment. Overall, we determined, for the first time, that SCFA mixture treatment might contribute to the accurate evaluation of the CYP3A4-dependent drug toxicity by improving metabolic activation, including CYP3A4 expression, of liver organoids.
Keyword
Liver organoidsHepatotoxicityInduced pluripotent stem cellsShort-chain fatty acids
ISSN
2073-4409
Publisher
MDPI
DOI
http://dx.doi.org/10.3390/cells10010126
Type
Article
Appears in Collections:
Division of Research on National Challenges > 1. Journal Articles
Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
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