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

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.

SUBMITTER: Oladimeji PO

PROVIDER: S-EPMC5402287 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Oladimeji Peter O PO Lin Wenwei W Brewer C Trent CT Chen Taosheng T

Scientific reports 20170424

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 ...[more]

PMID: 28436464

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Project description:Background and purposeRegulating P2X7 receptor-mediated activation of NLRP3 inflammasomes could be a therapeutic strategy to treat alcoholic hepatosteatosis. We investigated whether this process was modulated by gentiopicroside, the main active secoiridoid glycoside from Gentiana manshurica Kitagawa.Experimental approachIn vivo models of acute and chronic alcoholic hepatosteatosis were established by intragastrically administered ethanol or using chronic plus binge ethanol feeding of Lieber-DeCarli liquid diet to male C57BL/6 mice. In vitro, HepG2 cells were treated with ethanol. RAW 264.7 macrophages and murine bone marrow-derived macrophages (BMDMs) were stimulated with LPS and ATP.Key resultsIn both the acute and chronic alcohol-induced mouse hepatosteatosis models, gentiopicroside decreased serum aminotransferases and triglyceride accumulation. Up-regulated SREBP1, down-regulated PPARα and phosphorylated acetyl-CoA carboxylase caused by acute and chronic alcohol feeding were modulated by gentiopicroside, through the elevation of LKB1 and AMPK. Suppression of P2X7 receptor-NLRP3 activation by gentiopicroside inhibited IL-1β production. In ethanol-exposed HepG2 cells, gentiopicroside reduced lipogenesis and promoted lipid oxidation via activation of P2X7 receptor-NLRP3 inflammasomes. Genetic or pharmacological blockade of P2X7 receptors enhanced AMPK activity and reduced SREBP1 expression in ethanol-treated HepG2 cells. Gentiopicroside down-regulated P2X7 receptor-mediated inflammatory responses in LPS/ATP-stimulated RAW 264.7 macrophages and BMDMs. IL-1β from macrophages accelerated lipid accumulation in hepatocytes. Depleting macrophages by clodronate liposomes ameliorated alcoholic hepatosteatosis, and it was further alleviated by gentiopicroside.Conclusions and implicationsActivation of LKB1/AMPK signalling by gentiopicroside was mediated by the P2X7 receptor-NLRP3 inflammasome, suggesting the therapeutic value of blocking P2X7 receptors in the treatment of alcoholic hepatosteatosis.

Dataset Information

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

Publications

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

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