University of Oulu

Hassani-Nezhad-Gashti, F., Rysä, J., Kummu, O., Näpänkangas, J., Buler, M., Karpale, M., Hukkanen, J., Hakkola, J. (2018) Activation of nuclear receptor PXR impairs glucose tolerance and dysregulates GLUT2 expression and subcellular localization in liver. Biochemical Pharmacology, 148, 253-264. doi:10.1016/j.bcp.2018.01.001

Activation of nuclear receptor PXR impairs glucose tolerance and dysregulates GLUT2 expression and subcellular localization in liver

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Author: Hassani-Nezhad-Gashti, Fatemeh1,2; Rysä, Jaana3; Kummu, Outi1,2;
Organizations: 1Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu
2Medical Research Center Oulu, Oulu University Hospital and University of Oulu
3School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland
4Department of Pathology, Cancer Research and Translational Medicine Research Unit, University of Oulu and Oulu University Hospital
5Department of Internal Medicine, Research Unit of Internal Medicine, University of Oulu and Oulu University Hospital
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 2.3 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe201901101876
Language: English
Published: Elsevier, 2018
Publish Date: 2019-01-05
Description:

Abstract

Pregnane 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.

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Series: Biochemical pharmacology
ISSN: 0006-2952
ISSN-E: 1873-2968
ISSN-L: 0006-2952
Volume: 148
Pages: 253 - 264
DOI: 10.1016/j.bcp.2018.01.001
OADOI: https://oadoi.org/10.1016/j.bcp.2018.01.001
Type of Publication: A1 Journal article – refereed
Field of Science: 317 Pharmacy
Subjects:
GCK
PXR
Funding: The study was financially supported by the grants from the Academy of Finland (grant 286743 and 276747), the Novo Nordisk Foundation (grants NNF14OC0010653 and NNF15OC0015846), the Duodecim Society of Oulu, the Finnish Medical Foundation, the Finnish Foundation for Cardiovascular Research, and the Diabetes Research Foundation.
Academy of Finland Grant Number: 286743
276747
Detailed Information: 286743 (Academy of Finland Funding decision)
276747 (Academy of Finland Funding decision)
Copyright information: © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
  https://creativecommons.org/licenses/by-nc-nd/4.0/