title: Constitutive androstane receptor activation evokes the expression of glycolytic genes.
abstract: It is well-known that constitutive androstane receptor (CAR) activation by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) increases the liver-to-body weight ratio. CAR-mediated liver growth is correlated with increased expression of the pleiotropic transcription factor cMyc, which stimulates cell cycle regulatory genes and drives proliferating cells into S phase. Because glycolysis supports cell proliferation and cMyc is essential for the activation of glycolytic genes, we hypothesized that CAR-mediated up-regulation of cMyc in mouse livers might play a role in inducing the expression of glycolytic genes. The aim of the present study was to examine the effect of long-term CAR activation on glycolytic genes in a mouse model not subjected to metabolic stress. We demonstrated that long-term CAR activation by TCPOBOP increases expression of cMyc, which was correlated with reduced expression of gluconeogenic genes and up-regulation of glucose transporter, glycolytic and mitochondrial pyruvate metabolising genes. These changes in gene expression after TCPOBOP treatment were strongly correlated with changes in levels of glycolytic intermediates in mouse livers. Moreover, we demonstrated a significant positive regulatory effect of TCPOBOP-activated CAR on both mRNA and protein levels of Pkm2, a master regulator of glucose metabolism and cell proliferation. Thus, our findings provide evidence to support the conclusion that CAR activation initiates a transcriptional program that facilitates the coordinated metabolic activities required for cell proliferation.
authors.affiliation: The Institute of Molecular Biology and Biophysics, Novosibirsk, Timakova str., 2/12, 630117, Russia.
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Yarushkin
authors.affiliation: The Institute of Molecular Biology and Biophysics, Novosibirsk, Timakova str., 2/12, 630117, Russia.
authors.forename: Yuliya A
authors.initials: YA
authors.lastname: Kazantseva
authors.affiliation: Novosibirsk State University, Novosibirsk, Pirogova str., 2, 630090, Russia; Research Institute of Experimental and Clinical Medicine, Novosibirsk, Timakova str., 2, 630117, Russia.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Prokopyeva
authors.affiliation: Novosibirsk State University, Novosibirsk, Pirogova str., 2, 630090, Russia.
authors.forename: Diana N
authors.initials: DN
authors.lastname: Markova
authors.affiliation: Novosibirsk State University, Novosibirsk, Pirogova str., 2, 630090, Russia.
authors.forename: Yuliya A
authors.initials: YA
authors.lastname: Pustylnyak
authors.affiliation: The Institute of Molecular Biology and Biophysics, Novosibirsk, Timakova str., 2/12, 630117, Russia; Novosibirsk State University, Novosibirsk, Pirogova str., 2, 630090, Russia. Electronic address: pustylnyak@post.nsu.ru.
authors.forename: Vladimir O
authors.initials: VO
authors.lastname: Pustylnyak
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D000090702:Constitutive Androstane Receptor; D000072467:Cytochrome P450 Family 2 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D019289:Pyruvic Acid / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000378:metabolism; D013997:Time Factors
chemical_list: D000090702:Constitutive Androstane Receptor; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D019289:Pyruvic Acid; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D000072467:Cytochrome P450 Family 2; D005947:Glucose
keywords: Constitutive androstane receptor; Glycolic genes; Liver; Mitogen; TCPOBOP; cMyc