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Constitutive Androstane Receptor Agonist Initiates Metabolic Activity Required for Hepatocyte Proliferation

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Abstract

Activation of the constitutive androstane receptor (CAR, NR1I3) by chemical compounds induces liver hyperplasia in rodents. 1,4-Bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), a mouse CAR agonist, is most often used to study chemically induced liver hyperplasia and hepatocyte proliferation in vivo. TCPOBOP is a potent murine liver chemical mitogen, which induces rapid liver hyperplasia in mice independently of liver injury. In recent years, great amount of data has been accumulated on the transcription program that characterizes the TCPOBOP-induced hepatocyte proliferation. However, there are only few data about the metabolic requirements of hepatocytes that divide upon exposure to xenobiotics. In the present study, we have employed liquid chromatography – mass spectrometry technology combined with statistical analysis to investigate metabolite profile of small biomolecules, in order to identify key metabolic changes in the male mouse liver tissue after TCPOBOP administration. Analysis of biochemical pathways of the differentially affected metabolites in the mouse liver demonstrated significant TCPOBOP-mediated enrichment of several processes including those associated with nucleotide metabolism, amino acid metabolism, and energy substrate metabolism. Our findings provide evidence to support the conclusion that the CAR agonist, TCPOBOP, initiates an intracellular program that promotes global coordinated metabolic activities required for hepatocyte proliferation. Our metabolic data might provide novel insight into the biological mechanisms that occur during the TCPOBOP-induced hepatocyte proliferation in mice.

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Abbreviations

CAR:

constitutive androstane receptor

CYP2B :

gene encoding cytochrome P450 from subfamily 2B

TCPOBOP:

1,4-bis[2-(3,5-dichloropyridyloxy)] benzene

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Acknowledgments

The work was performed using equipment of the “Proteomic Analysis” Center for Collective Use supported by the Ministry of Science and Higher Education of the Russian Federation (agreement no. 075-15-2021-691).

Funding

The work was financially supported by the Russian Science Foundation (project no. 18-15-00021).

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Authors and Affiliations

  1. Novosibirsk State University, 630090, Novosibirsk, Russia

    Mark E. Mazin, Alina M. Perevalova, Yuliya A. Pustylnyak, Artem D. Rogachev, Elena A. Prokopyeva, Lyudmila F. Gulyaeva & Vladimir O. Pustylnyak

  2. Federal Research Center of Fundamental and Translational Medicine, 630117, Novosibirsk, Russia

    Mark E. Mazin, Andrei A. Yarushkin, Elena A. Prokopyeva, Lyudmila F. Gulyaeva & Vladimir O. Pustylnyak

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  1. Mark E. Mazin
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  2. Alina M. Perevalova
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  8. Vladimir O. Pustylnyak
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Contributions

V.O.P., L.F.G. – concept and supervision of the work; M.E.M., A.M.P., A.A.Ya., Yu.A.P., A.D.R., E.A.P. – experimental work and statistical processing of the results; M.E.M., A.A.Ya., V.O.P., L.F.G. – discussion of the research results; M.E.M. – writing the manuscript; V.O.P. – editing the manuscript.

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Correspondence to Vladimir O. Pustylnyak.

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The authors declare no conflict of interest in financial or any other sphere. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All experiments with animals were approved and performed as recommended by the Committee of Bioethics of the Federal Research Center for Fundamental and Translational Medicine (protocol no. 23-17).

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Mazin, M.E., Perevalova, A.M., Yarushkin, A.A. et al. Constitutive Androstane Receptor Agonist Initiates Metabolic Activity Required for Hepatocyte Proliferation. Biochemistry Moscow 88, 1061–1069 (2023). https://doi.org/10.1134/S0006297923080023

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