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Transcriptional regulation of carboxylesterase 1 (CES1) in human liver: role of the nuclear receptor NR1H3 (LXRα) and its splice isoforms

Joseph M Collins, Rong Lu, Xinwen Wang, Hao-Jie Zhu and Danxin Wang
Drug Metabolism and Disposition October 25, 2021, DMD-AR-2021-000649; DOI: https://doi.org/10.1124/dmd.121.000649
Joseph M Collins
1Pharmacotherapy and Translational Research, University of Florida, United States
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Rong Lu
2Department of Medicine, Stanford University, United States
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Xinwen Wang
3Northeast Ohio Medical University, United States
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Hao-Jie Zhu
4University of Michigan, United States
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Danxin Wang
1Pharmacotherapy and Translational Research, University of Florida, United States
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  • For correspondence: danxin.wang@cop.ufl.edu
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Abstract

Carboxylesterase 1 (CES1) is the predominant carboxylesterase in the human liver, involved in metabolism of both xenobiotics and endogenous substrates. Genetic or epigenetic factors that alter CES1 activity or expression are associated with changes in drug response, lipid, and glucose homeostasis. However, the transcriptional regulation of CES1 in the human liver remains uncertain. By applying both the random forest and Sobol's Sensitivity Indices (SSI) to analyze existing liver RNA expression microarray data (GSE9588), we identified NR1H3 (LXRα) as a key factor regulating constitutive CES1 expression. This model prediction was validated using siRNA knockdown and CRISPR-mediated transcriptional activation of NR1H3 in Huh7 and HepG2 cells. We found that NR1H3's activation of CES1 is splice isoform-specific, namely that increased expression of the NR1H3-211 isoform increased CES1 expression while NR1H3-201 did not. Also, in human liver samples, expression of NR1H3-211 and CES1 are correlated, while NR1H3-201 and CES1 are not. This trend also occurs during differentiation of induced pluripotent stem cells (iPSCs) to hepatocytes, where only expression of the NR1H3-211 isoform parallels expression of CES1. Moreover, we found that treatment with the NR1H3 agonist T0901317 in HepG2 cells had no effect on CES1 expression. Overall, our results demonstrate a key role of NR1H3 in maintaining the constitutive expression of CES1 in the human liver. Furthermore, our results support that the effect of NR1H3 is splice isoform-specific and appears to be ligand independent.

Significance Statement Despite the central role of CES1 in metabolism of numerous medications, little is known about its transcriptional regulation. Here we identify NR1H3 as a key regulator of constitutive CES1 expression, and therefore is a potential target for future studies to understand inter-person variabilities in CES1 activity and drug metabolism.

  • Alternative splicing/RNA editing
  • carboxylesterases
  • computational models
  • drug metabolism
  • Regulation - transcriptional
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 51 (2)
Drug Metabolism and Disposition
Vol. 51, Issue 2
1 Feb 2023
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Regulation of CES1 expression by NR1H3

Joseph M Collins, Rong Lu, Xinwen Wang, Hao-Jie Zhu and Danxin Wang
Drug Metabolism and Disposition October 25, 2021, DMD-AR-2021-000649; DOI: https://doi.org/10.1124/dmd.121.000649

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OtherArticle

Regulation of CES1 expression by NR1H3

Joseph M Collins, Rong Lu, Xinwen Wang, Hao-Jie Zhu and Danxin Wang
Drug Metabolism and Disposition October 25, 2021, DMD-AR-2021-000649; DOI: https://doi.org/10.1124/dmd.121.000649
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