Show simple item record

dc.contributor.authorHassani-Nezhad-Gashti, F
dc.contributor.authorRysä, J
dc.contributor.authorKummu, O
dc.contributor.authorNäpänkangas, J
dc.contributor.authorBuler, M
dc.contributor.authorKarpale, M
dc.contributor.authorHukkanen, J
dc.contributor.authorHakkola, J
dc.date.accessioned2018-04-23T12:01:15Z
dc.date.available2018-04-23T12:01:15Z
dc.date.issued2018
dc.identifier.urihttps://erepo.uef.fi/handle/123456789/6533
dc.description.abstractPregnane X receptor (PXR) is a nuclear receptor that senses chemical environment and is activated by numerous clinically used drugs and environmental contaminants. Previous studies have indicated that several drugs known to activate PXR appear to induce glucose intolerance. We now aimed to reveal the role of PXR in drug-induced glucose intolerance and characterize the mechanisms involved. We used PXR knockout mice model to investigate the significance of this nuclear receptor in the regulation of glucose tolerance. PXR ligand pregnenolone-16ɑ-carbonitrile (PCN) impaired glucose tolerance in the wildtype mice but not in the PXR knockout mice. Furthermore, DNA microarray and bioinformatics analysis of differentially expressed genes and glucose metabolism relevant pathways in PCN treated primary hepatocytes indicated that PXR regulates genes involved in glucose uptake. PCN decreased the expression of glucose transporter 2 (GLUT2) in mouse liver and in the wildtype mouse hepatocytes but not in the PXR knockout cells. Data mining of published chromatin immunoprecipitation-sequencing results indicate that Glut2 gene is a direct PXR target. Furthermore, PCN induced internalization of GLUT2 protein from the plasma membrane to the cytosol in the liver in vivo and repressed glucose uptake in the primary hepatocytes. Our results indicate that the activation of PXR impairs glucose tolerance and thus PXR represents a novel diabetogenic pathway. PXR activation dysregulates GLUT2 function by two different mechanisms. These findings may partly explain the diabetogenic effects of medications and environmental contaminants.
dc.language.isoEN
dc.publisherElsevier BV
dc.relation.ispartofseriesBIOCHEMICAL PHARMACOLOGY
dc.relation.urihttp://dx.doi.org/10.1016/j.bcp.2018.01.001
dc.rightsCC BY-NC-ND https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectPXR
dc.subjectGLUT2
dc.subjectGCK
dc.subjectimpaired glucose tolerance
dc.subjectdiabetes
dc.titleActivation of nuclear receptor PXR impairs glucose tolerance and dysregulates GLUT2 expression and subcellular localization in liver
dc.description.versionfinal draft
dc.contributor.departmentSchool of Pharmacy, Activities
uef.solecris.id51952710en
dc.type.publicationTieteelliset aikakauslehtiartikkelit
dc.rights.accessrights© Elsevier Inc
dc.relation.doi10.1016/j.bcp.2018.01.001
dc.description.reviewstatuspeerReviewed
dc.format.pagerange253-264
dc.relation.issn0006-2952
dc.relation.volume148
dc.rights.accesslevelopenAccess
dc.type.okmA1
uef.solecris.openaccessEi


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record