Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Sci Rep. 2017 Apr 24;7:46751. doi: 10.1038/srep46751.
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.
妊娠相关 X 受体 (PXR) 是一种异生物质受体，可调节肝脏中药物和外来化合物的解毒和清除。越来越多的证据表明药物代谢途径和能量代谢途径之间存在串扰，但对此交叉调节知之甚少。为了进一步阐明该研究中的能量代谢和药物代谢串扰，我们将 HepG2 细胞暴露于不同的葡萄糖浓度下。我们观察到高葡萄糖条件下 PXR 活性被诱导。这一发现与未经治疗的糖尿病患者药物清除率增加的先前临床报告一致。我们证明 AMP 激活蛋白激酶 (AMPK) 调节 PXR 转录活性，并且药理学上操纵 AMPK 激活与 PXR 活性呈反比关系。AMPK 的激活被证明下调 PXR 活性，并且与该结果一致，增强了细胞对药物的反应。总之，我们的结果描绘了一个迄今尚未报道的调节轴，涉及细胞的能量状态、PXR 调节和药物敏感性。
