PXR and Metabolism

Abstract

Pregnane X receptor (PXR) is a nuclear receptor initially characterized as a xenobiotic-sensing receptor that transcriptionally induces drug-metabolizing enzymes and transporters to control the disposition of xenobiotics. Emerging data reveal PXR's broader roles in regulating glucose and lipid metabolism to control metabolic homeostasis. In addition, there has been evidence of crosstalk among the PXR-regulated metabolism of drugs, lipids, and glucose. Such crosstalk might play roles in the development of diseases such as diabetes and cancer, and the therapeutic and toxic effects of drugs. The activity of PXR can be modulated by many structurally diverse chemicals. However, potent and selective chemical modulators of PXR was lacking. By using chemical biology, structural biology, and pharmacology approaches, we have developed a series of potent, selective and structurally related PXR modulators (i.e., agonists, antagonists, and inverse agonists). We discovered that subtle structural modifications of the compounds, or a mutation within the PXR ligand-binding domain can convert an antagonist to an agonist. While ligand binding affinity does not predict PXR's cellular activity, there is a correlation between ligand-induced positioning of the activation function 2 (AF-2) helix and PXR's transcriptional activity. We are using these novel chemical probes to investigate the broad metabolic function of PXR, with a goal to use them to develop therapies for PXR-regulated diseases.