Glucose-dependent regulation of pregnane X receptor is modulated by AMP-activated protein kinase

Peter O Oladimeji,C Trent Brewer,Wenwei Lin,Taosheng Chen

doi:10.1038/srep46751

Abstract

Pregnane X receptor (PXR) is a xenobiotic receptor that regulates the detoxification and clearance of drugs and foreign compounds from the liver. There has been mounting evidence of crosstalk between the drug metabolism pathway and the energy metabolism pathway, but little is known about this cross-regulation. To further delineate the energy metabolism and drug metabolism crosstalk in this study, we exposed HepG2 cells to varying glucose concentrations. We observed that PXR activity was induced under high-glucose conditions. This finding is consistent with previous clinical reports of increased drug clearance in patients with untreated diabetes. We demonstrated that AMP-activated protein kinase (AMPK) modulates PXR transcriptional activity and that pharmacologically manipulated AMPK activation exhibits an inverse relation to PXR activity. Activation of AMPK was shown to downregulate PXR activity and, consistent with that, potentiate the response of cells to the drug. Taken together, our results delineate a hitherto unreported axis of regulation that involves the energy status of the cell, PXR regulation, and drug sensitivity.

Highlights

Pregnane X receptor (PXR) is a xenobiotic receptor that regulates the detoxification and clearance of drugs and foreign compounds from the liver
The previously reported evidence that drug clearance was significantly increased in patients with untreated type I diabetes, an effect that was reversed by insulin treatment[13,14], coupled with evidence from the mouse model of diabetes in which mice exhibited increased basal expression of cytochrome P450 (CYP) enzyme that was corrected by insulin administration[15], prompted us to assess the direct regulation of pregnane X receptor (PXR) by glucose in vitro
To determine if PXR was involved in the glucose-dependent regulation of CYP3A4, HepG2 PXR CYP-luc cells were transfected with either control siRNA (NT siRNA) or siRNA targeting PXR (PXR siRNA) for 48 h to knock down PXR (Fig. 1d)

Summary

Introduction

Pregnane X receptor (PXR) is a xenobiotic receptor that regulates the detoxification and clearance of drugs and foreign compounds from the liver. We observed that PXR activity was induced under high-glucose conditions This finding is consistent with previous clinical reports of increased drug clearance in patients with untreated diabetes. Drug metabolism is regulated by numerous drug-metabolizing enzymes (DMEs) and drug transporters such as cytochrome P450 (CYP) enzyme 3 A, CYP2B, CYP2C, aldehyde dehydrogenase, alcohol dehydrogenase, carboxylesterase, UDP-glucuronosyltransferase (UGT) 1A1, sulfotransferase, multidrug resistance protein (MDR) 1, ATP-binding cassette transporter C (ABCC) 2, and organic anion transporting polypeptide (OATP) 2 (refs 2–6) Differential expression of these DMEs and drug transporters is, a major determinant of the variability in drug response between individuals[7]. The most abundant hepatic and intestinal phase I enzyme is CYP3A4, which metabolizes approximately 50% of marketed drugs It is a primary transcriptional target of PXR9; its activity is modulated by a variety of factors, including food components. This observation is consistent with studies conducted in a mouse model of type I diabetes, in which the mice exhibited increased CYP2B10 basal expression that was corrected by insulin www.nature.com/scientificreports/

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