Combining Genomics To Identify the Pathways of Post-Transcriptional Nongenotoxic Signaling and Energy Homeostasis in Livers of Rats Treated with the Pregnane X Receptor Agonist, Pregnenolone Carbonitrile

Transcriptomic, proteomic, phosphoproteomic,
and metabolomic analyses
were combined to determine the role of pregnane X receptor (PXR) in
nongenotoxic signaling and energy homeostasis in liver after rats
were repeatedly orally dosed with the PXR agonist pregnenolone carbonitrile
(PCN) for 7 days. Analyses of mRNAs and proteins in the supernatant,
membrane, and cytosolic fractions of enlarged liver homogenates showed
diverse expression profiles. Gene set enrichment analysis showed that
the synchronous increase in mRNAs and proteins involved in chemical
carcinogenesis and the response to drug was possibly mediated by the
PXR pathway and proteasome core complex assembly was possibly mediated
by the Nrf2 pathway. In addition, levels of proteins in the endoplasmic
reticulum lumen and involved in the acute-phase response showed specific
increase with no change in mRNA level, and those composed of the mitochondrial
inner membrane showed specific decrease. The analysis of phosphorylated
peptides of poly­(A) RNA binding proteins showed a decrease in phosphorylation,
possibly by casein kinase 2, which may be related to the regulation
of protein expression. Proteins involved in insulin signaling pathways
showed an increase in phosphorylation, possibly by protein kinase
A, and those involved in apoptosis showed a decrease. Metabolomic
analysis suggested the activation of the pentose phosphate and anaerobic
glycolysis pathways and the increase of amino acid and fatty acid
levels, as occurs in the Warburg effect. In conclusion, the results
of combined analyses suggest that PXR’s effects are due to
transcriptional and post-transcriptional regulation with alteration
of nongenotoxic signaling pathways and energy homeostasis.