Constitutive androstane receptor agonist initiates metabolic activity required for hepatocite proliferation

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