Convergence of Multiple Nuclear Receptor Signaling

Abstract

This chapter will describe the actions of the xenosensors peroxisome proliferator-activated receptor (PPAR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), arylhydrocarbon receptor (AhR), and nuclear factor (erythroid-derived 2) (NF-E2)-related factor-2 (Nrf2) that regulate gene expression of the foreign compound-metabolizing enzymes. In this chapter, we provide evidence that they also interact with other signaling pathways that control nutrient metabolism. We have described the potential mechanisms through which regulation of intermediary metabolism converges with the regulation of foreign compound metabolism. The xenosensors regulate foreign compound metabolism directly through transcriptional activation of target genes and indirectly by interacting with other transcription factors to alter function, by competing for binding to cis-acting elements, or by endocrine disruption through metabolism of ligand precursors and clearance of ligand activators, thereby terminating their biological function. Cross talk between the xenobiotic and metabolic nuclear receptors suggests coordinate regulation between nutrient and foreign compound metabolism. Newly identified functional interactions with key metabolic regulators, including the forkhead transcription factors, steroid regulatory element binding protein (SREBP), and others, suggest that metabolic disorders such as starvation, obesity, metabolic syndrome, and diabetes that alter metabolic homeostasis also alter foreign compound metabolism and vice versa. Foreign compound exposure may predispose individuals to metabolic disease through these mechanisms of interaction.