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Open AccessArticle

Effect of Microbial Short-Chain Fatty Acids on CYP3A4-Mediated Metabolic Activation of Human Pluripotent Stem Cell-Derived Liver Organoids

1
Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea
2
Department of Functional Genomics, Korea University of Science & Technology (UST), 217 Gajungro, Yuseong-gu, Daejeon 34113, Korea
3
Biomedical Translational Research Center, KRIBB, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea
*
Authors to whom correspondence should be addressed.
Cells 2021, 10(1), 126; https://doi.org/10.3390/cells10010126
Received: 29 September 2020 / Revised: 19 December 2020 / Accepted: 6 January 2021 / Published: 11 January 2021
(This article belongs to the Section Stem Cells)
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. View Full-Text
Keywords: liver organoids; hepatotoxicity; induced pluripotent stem cells; short-chain fatty acids liver organoids; hepatotoxicity; induced pluripotent stem cells; short-chain fatty acids
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MDPI and ACS Style

Mun, S.J.; Lee, J.; Chung, K.-S.; Son, M.-Y.; Son, M.J. Effect of Microbial Short-Chain Fatty Acids on CYP3A4-Mediated Metabolic Activation of Human Pluripotent Stem Cell-Derived Liver Organoids. Cells 2021, 10, 126. https://doi.org/10.3390/cells10010126

AMA Style

Mun SJ, Lee J, Chung K-S, Son M-Y, Son MJ. Effect of Microbial Short-Chain Fatty Acids on CYP3A4-Mediated Metabolic Activation of Human Pluripotent Stem Cell-Derived Liver Organoids. Cells. 2021; 10(1):126. https://doi.org/10.3390/cells10010126

Chicago/Turabian Style

Mun, Seon J.; Lee, Jaeseo; Chung, Kyung-Sook; Son, Mi-Young; Son, Myung J. 2021. "Effect of Microbial Short-Chain Fatty Acids on CYP3A4-Mediated Metabolic Activation of Human Pluripotent Stem Cell-Derived Liver Organoids" Cells 10, no. 1: 126. https://doi.org/10.3390/cells10010126

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