TY - JOUR

T1 - Constitutive Androstane Receptor Agonist Initiates Metabolic Activity Required for Hepatocyte Proliferation

AU - Mazin, Mark E

AU - Perevalova, Alina M

AU - Yarushkin, Andrei A

AU - Pustylnyak, Yuliya A

AU - Rogachev, Artem D

AU - Prokopyeva, Elena A

AU - Gulyaeva, Lyudmila F

AU - Pustylnyak, Vladimir O

N1 - 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). The work was financially supported by the Russian Science Foundation (project no. 18-15-00021).

PY - 2023/8

Y1 - 2023/8

N2 - 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.

AB - 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.

KW - Animals

KW - Male

KW - Mice

KW - Cell Proliferation

KW - Constitutive Androstane Receptor/agonists

KW - Hepatocytes/metabolism

KW - Hyperplasia/metabolism

KW - Liver/metabolism

KW - Mice, Inbred C57BL

KW - Receptors, Cytoplasmic and Nuclear/metabolism

KW - hepatocyte

KW - liver

KW - constitutive androstane receptor

KW - metabolomics

KW - TCPOBOP

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85168462255&origin=inward&txGid=cfd124aa82637a8f1a30580398bab88b

UR - https://www.mendeley.com/catalogue/c8f21506-170d-3250-8b0d-b191a3904357/

U2 - 10.1134/S0006297923080023

DO - 10.1134/S0006297923080023

M3 - Article

C2 - 37758307

VL - 88

SP - 1061

EP - 1069

JO - Biochemistry (Moscow)

JF - Biochemistry (Moscow)

SN - 0006-2979

IS - 8

ER -